臺灣博碩士論文加值系統

乳腺停止泌乳後，多形核嗜中性白血球 (polymorphonuclear leukocyte, PMN）會匯集至乳腺，使體細胞PMN之比例上升。基質金屬蛋白酶（Matrix metalloproteinase, MMPs）已知關係許多生理過程之組織重整，其中，存在於PMN分泌顆粒內的MMP-9對於降解基底膜的主要成分type Ⅳ collagen扮演了重要的角色。而腫瘤壞死因子（Tumor necrosis factor α, TNF-α）亦可由PMN分泌，經自泌/旁泌機制活化細胞內mitogen-activated protein kinase（MAPK）family進而增加MMP-9的釋放。本研究之目的為探討MMP-9在乳牛乳腺乾乳過程之角色，及同時體細胞中PMN上TNF-α自泌調控MMP-9分泌之機制。本研究以6隻乳牛為試驗動物，每週一次，收集乾乳後0-3週的乳腺分泌物，脫脂分離後收集乳清及體細胞。正常泌乳期的乳汁也取樣作為對照，測定乳清中MMP-9、TNF-α含量之變化與體細胞上TNF-α及MAPK家族的表現及活化程度。結果發現總體細胞數在乾乳後1週呈顯著及迅速上升，並持續上升至第3週。MMP-9在泌乳期乳汁中測不到活性，乾乳期則觀測到乳清中MMP-9活性隨著乾乳的進行顯著的上升；而MMP-2在泌乳期乳汁中即有活性，乾乳後MMP-2活性則維持高的水準。經過計算，MMP-9與MMP-2的比例隨乾乳的進行逐漸增加，顯見MMP-9在乳腺退化過程佔有重要的角色。乾乳期乳清中TNF-α含量隨著乾乳的進行逐漸降低，均明顯低於泌乳期之乳汁。體細胞中MAPK family、TNF-α之表現以Western blot測定時發現泌乳階段之體細胞上26 kDa TNF-α相對於17 kDa TNF-α之表現量高於乾乳期，推測因為泌乳期體細胞上17 kDa TNF-α已釋出至乳中，此點可由泌乳期乳清中17 kDa TNF-α含量高於乾乳期得到印證。乾乳期間體細胞上26 kDa TNF-α及17 kDa TNF-α的表現在乾乳後1週皆顯著高於乾乳第0週，之後則無差異。乾乳期間體細胞上磷酸化的ERK、p38與JNK相對於未磷酸化ERK、p38與JNK的比值，與乾乳第0週相較均無顯著差異，因此乾乳開始至乾乳3週之內，MAPK各家族活化程度沒有明顯變化。在in vitro試驗中，將乳牛血液分離之PMN經乾乳分泌物刺激30 min後，PMN所釋出的MMP-9明顯較未受乾乳分泌物刺激者增加至1.6倍，此升高現象會被p38抑制劑部分抵消，但不會被TNF-α 抗體所抵消。另外，乾乳乳腺分泌物處理30 min後，PMN釋出之17 kDa TNF-α相較未受乾乳分泌物處理者增加至6.1倍，此作用會被p38抑制劑部分抵消，因此乾乳乳腺分泌物似乎可藉由活化PMN細胞內p38 MAPK的路徑來增加TNF-α及MMP-9的釋出，但MMP-9之分泌與TNF-α之自泌/旁泌無關。

综合以上結果，乳牛乾乳之後體細胞的數目及乳清中MMP-9含量持續增加，顯示體細胞及其所釋出之MMP-9在乾乳過程的重要性。體細胞釋出MMP-9及TNF-α會部份經由活化PMN中p38 MAPK路徑，有助於退化期間乳腺的重整及免疫，而乾乳乳腺分泌物中具有活化PMN的成分有待進ㄧ步確認。

An influx of polymorphonuclear neutrophils (PMN) immediately after drying-off was observed to increase the proportion of PMN of somatic cell counts (SCC) of bovine mammary gland. Matrix metalloproteinases (MMPs) involve in the remodeling of tissue under many physiological circumstances. PMN is the richest source of the MMP-9, which functions to degrade collagen Ⅳ of basement membrane proteins during tissue remodeling. It was also demonstrated that tumor necrosis factor-α (TNF-α) released by PMN can induce mitogen-activated protein kinase (MAPK) mediated-MMP-9 degranulation. The objectives of this study were to determine the involvement of MMP-9 in involution of cow mammary gland after drying-off and to assess the mechanisms by which MMP-9 might be regulated by TNF-α via autocrine/paracrine loop. Six cows were used to provide weekly mammary secretion samples from 0-3 weeks after milk-stasis. Skimmed mammary secretion were used to prepare serum and somatic cells to evaluate the alteration of content of MMP-9 and TNF-α in serum, the expression and activation of MAPK pathways of somatic cells after drying-off. Results show that SCC of mammary dry secretion abruptly increased at wk 1 and continued climbing up to wk 3. MMP-9 was not detected in regular milk but appeared at wk 0 and elevated significantly thereafter. MMP-2, on the other hand, was detected both in regular milk and dry secretion, only was higher during the latter period. The increasing MMP-9/MMP-2 ratio in mammary tissue after milk stasis suggests a greater contribution of MMP-9 to mammary involution. Content of 17kDa TNF-α in serum of dry secretion was lower than regular milk and decreased along the dry period. The expressions of MAPK family and TNF-α on somatic cells as revealed by Western blot show that less 17 kDa TNF-α relative to 26 kDa TNF-α was expressed on somatic cells of regular milk compared to that of dry glands, confirming that greater amount of 17 kDa TNF-α was released from somatic cells during lactation. The ratio of expression of phosphorylated to unphosphorylated MAPK family remained similar to wk 0 throughout dry period which suggest no MAPK pathway. Results of in vitro studies indicate that mammary dry secretion stimulated MMP-9 degranulation from PMN to 1.6 folds after 30 min incubation, which was partially abolished in the presence of p38 inhibitor but was not for anti-TNF-α antibody. A 6.1 folds of stimulatory effect on TNF-α release was observed under similar incubation environment, so did the effect of p38 inhibitor. It is postulated that the release of MMP-9 and TNF-α from PMN is partially mediated by MAPK pathway and is TNF-α autocrine/paracrine loop independent. In conclusion, SCC and MMP-9 in mammary lumen continuously increase after milk stasis of dairy cows implying their close association with mammary gland involution. The release of MMP-9 and TNF-α from somatic cells during mammary gland involution is partially mediated by activation of MAPK pathway to collaborate tissue remodeling and boost glandular immunity. The bioactive components of dry mammary secretion which promote these functions of somatic cells warrant further identification.

目次
壹、前言 1
貳、文獻檢討 2
ㄧ、乳腺組織的發育與重整 2
（一）乳腺的形態及組織學 2
（二）腺泡的發育 2
（三）乳腺泌乳與乾乳的週期 5
二、乳中體細胞 (Somatic cell) 與乳腺退化的關係 7
（一）PMN之種類與功能 8
（二）PMN的顆粒 10
（三）PMN之應用 10
（四）PMN與酪蛋白水解物影響乳腺的退化 13
三、MMPs與乳腺退化 14
（一）MMPs之家族成員 14
（二）MMPs之基本結構 16
（三）MMP-9 18
四、TNF-α參與乳腺退化之可能角色
（一）化學構造 21
（二）生理功能 21
（三）TACE (Tumor necrosis factor-α converting enzyme) 22
（四）TNF-α 之細胞內訊號傳導路徑 24
（五）TNF-α與MAP kinase的活化 27
（六）TNF-α刺激MMP-9的產生 28
五、MAP kinase 28
（一）Extracellular signal-regulated kinase (ERK1/2或p44/42 MAP
kinase) 28
（二）p38 MAP kinase (CSBP、RK或mpk2) 31
（三）The stress-activated protein kinase (JNKs、SAPK或 c-Jun kinase)
31
（四）MAPK活化路徑 32
（五）MAPK pathway與MMP-9的關係 34
參、材料與方法 35
ㄧ、試驗動物飼養管理與樣品蒐集 35
二、藥品來源 35
三、蛋白質定量測定 37
（一）標準曲線製作 37
（二）樣品濃度之測定 38
四、乳中體細胞與milk serum分離 38
五、乾乳後不同週次分泌物中體細胞及乳清樣品之製備 38
（一）試劑配製 38
（二）Cell lysate 的製備 39
（三）乳清之濃縮 39
六、乾乳後不同週次分泌物乳清中Gelatinase B 之活性測定 (Zymography)
40
（ㄧ）試劑配製 40
（二）Gelatinase marker 40
（三）步驟 41
七、乾乳後不同週次分泌物之乳清中TNF-α 表現 (Western blot) 41
（一） 試劑配製 41
（二） 步驟 42
八、乾乳後不同週次分泌物之體細胞中MAP kinases 磷酸化程度 43
九、乾乳後不同週次分泌物之體細胞中TNF-α表現 43
十、PMN試管中分泌TNF-α及MMP-9試驗樣本之製備 44
（一） 試劑配製 44
（二）PMN的製備 44
十一、乾乳上清液對PMN釋出Gelatinase B表現影響 45
（ㄧ）試驗處理 45
（二）步驟 45
十二、乾乳上清液對PMN釋出TNF-α表現影響 (Western blot） 46
（一）上清培養液中之17 kDa TNF-α 製備 46
（二）步驟 46
十三、統計分析 46
肆、結果 47
ㄧ、乾乳階段乳腺分泌物中體細胞數 (MSCC) 之相對變化 47
二、乾乳期間乳腺分泌物之分析 47
（一）乾乳期間gelatinase 活性的變化 47
（二）乾乳期間乳腺分泌物中17kDa TNF-α相對含量的變化 48
三、乾乳階段乳腺分泌中體細胞之分析 53
（一）泌乳期與乾乳階段體細胞TNF-α與MAPK family活化情形 53
（二）乾乳0至3週乾乳分泌物中體細胞TNF-α相對含量比 53
（三）體細胞內MAPK family 活化 (磷酸化) 程度於乳腺乾乳階段
之變化 56
四、乾乳乳腺上清液在試管中 (in vitro) 對PMN 釋放MMP-9的調控 59
（一）不同時間下乾乳上清液在試管中 (in vitro) 對PMN釋放
MMP-9表現的調控 (time dependent) 59
（二） 不同濃度下乾乳上清液在試管中 (in vitro) 對PMN釋放
MMP-9表現的調控 62
（三）乾乳上清液在試管中 (in vitro) 受到TNF-α 抗體與MAPK
的抑制劑對PMN分泌MMP-9的影響 62
五、乾乳乳腺上清液在試管中 (in vitro) 對PMN釋放TNF-α表現的
調控 65
伍、討論 67
陸、結論 71
柒、參考文獻 73



圖表目次
Table 1. Classification of leukocyte proteinases according to catalytic mechanism 12
Figure 1. General morphology of the fully developed bovine mammary gland. 3
Figure 2. Lactating tissue with functional secreting epithelium structures in the mammary gland 4
Figure 3. The granule diversity in PMN 11
Figure 4. Schematic structure of MMPs 17
Figure 5. The activation network of gelatinase B by MMPs 20
Figure 6. Domain structure of TACE and physiological function of TACE 23
Figure 7. Proximal components of the tumor necrosis factor (TNF) receptor type 1 (TNFR1), TNF receptor type 2 (TNFR2) and Fas signal-transduction pathways and their relationships to the activation and inhibition of programmed cell death and inflammation 25
Figure 8. Intracellular signaling pathways that contribute to gelatinase (A and) B gene transcription 29
Figure 9. Flow chart of the three MAPK modules (ERKs, JNKs, p38) 30
Figure 10. The mitogen-activated protein kinase (MAPK) core signaling module 33
Figure 11. Relative Change of microscopic somatic cell counts (MSCC) of mammary secretions after milk stasis. 49
Figure 12. Standards of MMP-2/MMP-9 were paralleled with human gelatinase marker and MMP-9 expression of bovine mammary gland during lactation and involution period 50
Figure 13. MMP-9 expressions of bovine mammary gland during lactation and involution period. 51
Figure 14. TNF-α expression of bovine mammary gland secretions 52
Figure 15. Activation of MAP kinase and TNF-α expression in somatic cells of mammary gland secretions during lactation stage and at week 0, 1, 2, 3 after milk stasis. 54
Figure 16. Tumor necrosis factor α expressions of bovine somatic cells during
mammary involution. 55
Figure 17. p44/42 MAP kinase activation of bovine somatic cells during
mammary involution. 57
Figure 18. p38 MAP kinase activation of bovine somatic cells during mammary involution. 58
Figure 19. JNK MAP kinase activaion of bovine somatic cells during mammary involution. 60
Figure 20. Time-course of MMP-9 protein secretion in PMN after mammary gland dry secretion stimulation 61
Figure 21. Dose effect of mammary gland dry secretion on MMP-9 protein secretion. 63
Figure 22. Effect of mammary gland dry secretion on MMP-9 secretion of PMN through MAPK signaling pathway 64
Figure 23. Effect of mammary gland dry secretion on TNF-α expression of PMN and the inhibitory effects of p38 inhibitor 66

周文科。2006。乳牛多形核嗜中性白血球上TNF-α自泌調控血纖維酶原活化系統對乳腺組織重組之探討。碩士論文。國立中興大學，台中市。
Abraham, E., and M. R. Gyetko, K. Kuhn, J. Arcaroli, D. Strassheim, J. S. Park, S. Shetty, and S. Idell. 2003. Urokinase-type plasminogen activator potentiates lipopolysaccharide-induced neutrophil activation. J. Immunol. 170:5644-5651.
Akgul, C., and S. W. Edwards. 2003. Regulation of neutrophil apoptosis via death receptors. Cell Mol. Life Sci. 60:2402-2408.
Annen, E. L., R. J. Collier, M. A. Mcguire, and J. L. Vincini. 2004. Effects of dry period length on milk yield and mammary epithelial cells. J. Dairy Sci. 87:6-76.
Aslam, M., R. Jimenex-Flores, H. Y. Kim, and W. L. Hurley. 1994. Two dimensional electrophoretic analysis of proteins of bovine mammary gland secretions collected during the dry period. J. Dairy Sci. 77:1529-1536.
Aslam, M., and W. L. Hurley. 1997. Proteolysis of milk proteins during involution of the bovine mammary gland. J. Dairy Sci. 80:2004-2010.
Aslam, M., and W. L. Hurley. 1998. Peptides generated from milk proteins in the bovine mammary gland during involution. J. Dairy Sci. 81:748-755.
Athie, F., K. C. Bachman, H. H. Head, M. J. Hayen, and C. J. Wilcox. 1997. Milk plasmin during bovine mammary involution that has been accelerated by estrogen. J. Dairy Sci. 80:1561-1568.
Bartholomé, E. J., I. Van Aelst, E. Koyen, R. Kiss, F. Willems, M. Goldman, and G. Opdenakker. 2001. Human monocyte-derived dendritic cells produce bioactive gelatinase B: inhibition by IFN-beta. J. Interferon. Cytokine Res. 21:495–501.
Basset, P., J. P. Bellocq, C. Wolf, I. Stoll, P. Hutin, J. M. Limacher, O. L. Podhajcer, M. P. Chenard, M. C. Rio, and P. Chambon. 1990. A novel metalloproteinase gene specifically expressed in stromal cells of breast carcinomas. Nature. 348:699-704.
Baud, V., Z. G. Liu, B. Bennett, N. Suzuki, Y. Xia, and M. Karin. 1999. Signaling by proinflammatory cytokines: oligomerization of TRAF2 and TRAF6 is sufficient for JNK and IKK activation and target gene induction via an amino-terminal effector domain. Genes Dev. 13:1297-1308.
Baud, V., and M. Karin. 2001. Signal transduction by tumor necrosis factor and its relatives. Trends Cell Biol. 11:372-377.
Benaud, C., R. B. Dickson, and E. W. Thompson. 1998. Roles of the matrix metalloproteinases in mammary gland development and cancer. Breast Cancer Res. Treat. 50:97-116.
Birkedal-Hansen H., W. G. M., M. K. Bodden, L. J. Windsor, B. Birkedal-Hansen, A. DeCarlo, and J. A. Engler. 1993. Matrix metalloproteinases: a review. Crit. Rev. Oral. Biol. Med. 4:197-250.
Black, R. A., C. T. Rauch, C. J. Kozlosky, J. J. Peschon, J. L. Slack, M. F. Wolfson, B. J. Castner, K. L. Stocking, P. Reddy, S. Srinivasan, N. Nelson, N. Boiani, K. A. Schooley, M. Gerhart, R. Davis, J. N. Fitzner, R. S. Johnson, R. J. Paxton, C. J. March, and D. P. Cerretti. 1997. A metalloproteinase disintegrin that releases tumour-necrosis factor-α from cells. Nature. 385:729-733.
Black, R. A. 2002. Tumor necrosis factor-α converting enzyme. Int. J. Biochem. Cell Biol. 34:1-5.
Blackburn, P. S. 1966. The variation in the cell count of cow''s milk throughout lactation and from one lactation to the next. J. Dairy Res. 33:193-198.
Bombini, G., C. Canetti, F. A. Rocha, and F. Q. Cunha. 2004. Tumour necrosis factor-α mediates neutrophil migration to the knee synovial cavity during immune inflammation. Eur. J. Pharmacol. 496:197-204.
Bond, M., R. P. Fabunmi, A. H. Baker, and A. C. Newby. 1998. Synergistic upregulation of metalloproteinase-9 by growth factors and inflammatory cytokines: an absolute requirement for transcription factor NF-kappa B. FEBS Lett. 435:29-34.
Bond, M., A. J. Chase, A. H. Baker, and A. C. Newby. 2001. Inhibition of transcription factor NF-kappaB reduces matrix metalloproteinase-1, -3 and -9 production by vascular smooth muscle cells. Cardiovasc. Res. 50:556-565.
Borregaard, N., L. Kjeldsen, K. Rygaard, L. Bastholm, M. H. Nielsen, H. Sengelov, O. W. Bjerrum, and A. H. Johnsen. 1992. Stimulus-dependent secretion of plasma proteins from human neutrophils. J. Clin. Invest. 90:86-96.
Borregaard, N., M. Sehested, B. S. Nielsen, H. Sengelov, and L. Kjeldsen. 1995. Biosynthesis of granule proteins in normal human bone marrow cells. Gelatinase is a marker of terminal neutrophil differentiation. Blood. 85:812-817.
Borregaard, N., and J. B. Cowland. 1997. Granules of the human neutrophilic polymorphonuclear leukocyte. Blood. 89:3503-3521.
Brockhaus, M., H. J. Schoenfeld, E. J. Schlaeger, W. Hunziker, W. Lesslauer, and H. Loetscher 1990. Identification of two types of tumor necrosis factor receptors on human cell lines by monoclonal antibodies. Proc. Natl. Acad. Sci. USA. 87:3127-3131.
Brolund, L. 1985. Cell counts in bovine milk: causes of variation and applicability for diagnosis of subclinical mastitis. Acta Vet. Scand. 80:1-123.
Burvenich, C., A. J. Guidry, and M. J. Paape. 1995. Natural defence machanisms of the lactating and dry mammary gland (overview paper). Proc. 3rd IDF. Int. Mastitis Seminar, Tel Aviv, Israel.
Buxbaum, J. D., K. N. Liu, Y. Luo, J. L. Slack, K. L. Stocking, J. J. Peschon, R. S. Johnson, B. J. Castner, D. P. Cerretti, and R. A. Black. 1998. Evidence that tumor necrosis factor-α converting enzyme is involved in regulated α-secretase cleavage of the Alzheimer amyloid protein precursor. J. Biol. Chem. 273:27765-27767.
Capuco, A. V., and R. M. Akers. 1999. Mammary involution in dairy animals. J. Mammary Gland Biol. Neoplasia. 4:137-144.
Capuco, A. V., and S. Ellis. 2005. Bovine mammary progenitor cells: current concepts and future directions. J. Mammary Gland Biol. Neoplasia. 10:5-15.
Cassatella, M. A. 1995. The production of cytokines by polymorphonuclear neutrophils. Immunol. Today. 16:21-26.
Chakrabarti, S., and K. D. Patel. 2005. Regulation of matrix metalloproteinase-9 release from IL-8-stimulated human neutrophil. J. Leukoc. Biol. 78:279-288.
Chakrabarti, S., J. M. Zee, and K. D. Patel. 2006. Regulation of matrix metalloproteinase-9 (MMP-9) in TNF-stimulated neutrophils: novel pathways for tertiary granule release. J. Leukoc. Biol. 79:214-222.
Chandler, S., J. Cossin, J. Lury, and G. Wells. 1996. Macrophage metalloelastase degrades matrix and myelin proteins and processes a tumor necrosis factor-α fusion protein. Biochem. Biophys. Res. Commun. 228:421-429.
Chandler, S., K. M. Miller, J. M. Clements, J. Lury, D. Corkill, D. C. Anthony, S. E. Adams, A. J. Gearing. 1997. Matrix metalloproteinases, tumor necrosis factor and multiple sclerosis: an overview. J. Neuroimmunol. 72:155-161.
Chang, L., and M. Karin. 2001. Mammalian MAP kinase signalling cascades. Nature.
410:37-40.
Chen, W. N., R. L. Woodbury, L. E. Kathmann, L. K. Opresko, R. C. Zangar, H. S. Wiley, and B. D. Thrall. 2004. Induced autocrine signaling through the epidermal growth factor receptor contributes to the response of mammary epithelial cells to tumor necrosis factor α . J. Biol. Chem. 279:18488-18496.
Chen, Z., T. B. Gibson, F. Robinson, L. Silvestro, G. Pearson, B. Xu, A. Wright, C. Vanderbilt, and M. H. Cobb. 2001. MAP kinases. Chem. Rev. 101:2449-2476.
Chinnaiyan, A. M., K. O''Rourke, M. Tewari, and V. M. Dixit. 1995. FADD, a novel death domain-containing protein, interacts with the death domain of Fas and initiates apoptosis. Cell. 81:505-512.
Choo, M-K., H. Sakurai, K. Koizumi, and I. Saiki. 2006. TAK1-mediated stress signaling pathways are essential for TNF-α-promoted pulmonary metastasis of murine colon cancer cells. Int. J. Cancer. 118:2758-2764.
Clark, A. R., J. L. Dean, and J. Saklatvala. 2003. Post-transcriptional regulation of gene expression by mitogen-activated protein kinase p38. FEBS Lett. 546:37-44.
Cobb, M., and E. J. Goldsmith. 1995. How MAP kinases are regulated. J. Biol. Chem. 270:14843-14846.
Cowan, K. J., and K. B. Storey. 2003. Mitogen-activated protein kinases: new signaling pathways functioning in cellular responses to environmental stress. J. Exp. Biol. 206:1107-1115.
Cowland, J. B., and N. Borregaard. 1999. The individual regulation of granule protein mRNA levels during neutrophil maturation explains the heterogeneity of neutrophil granules. J. Leukoc. Biol. 66:989-995.
Davis, R. J. 1993. The mitogen-activated protein kinase signal transduction pathways. J. Biol. Chem. 268:14553-14556.
Davis, R. J. 2000. Signal transduction by the JNK group of MAP Kinases. Cell.
103:239-252.
Decleva, E., P. Dri, R. Menegazzi, S. Busetto, and R. Cramer. 2002. Evidence that TNF-induced respiratory burst of adherent PMN is mediated by integrin {α}L{β}2. J. Leukoc. Biol. 72:718-726.
Delclaux, C., C. Delacourt, M-P. d''Ortho, V. Boyer, C. Lafuma, and A. Harf. 1996. Role of gelatinase B and elastase in human polymorphonuclear neutrophil migration across basement membrane. Am. J. Respir. Cell Mol. Biol. 14:288-295.
Denhardt, D. T. 1996. Signal-transducing protein phosphorylation cascades mediated by Ras/Rho proteins in the mammalian cell: the potential for multiple signalling. Biochim. J. 318:729-747.
Devin, A., A. Cook, Y. Lin, Y. Rodriguez, M. Kelliher, and Z-G. Liu. 2000. The distinct roles of TRAF2 and RIP in IKK activation by TNF-R1: TRAF2 recruits IKK to TNF-R1 while RIP mediates IKK activation. Immunity. 12:419-429.
Doedens, J. R., and R. A. Black. 2000. Stimulation-induced down-regulation of tumor necrosis factor-α converting enzyme. J. Biol. Chem. 275:14598-14607.
Elion, E. A., P. L. Grisafi, and G. R. Flink, 1990. FUS3 encodes a cdc2+/CDC28-related kinase required for the transition from mitosis into conjugation. Cell. 60:649-664.
Fan, H., and R. Derynck. 1999. Ectodomain shedding of TGF-α and other transmembrane proteins is induced by receptor tyrosine kinase activation and MAP kinase signaling cascades. EMBO J. 18:6962-6972.
Fata, J. E., K. J. Leco, R. A. Moorehead, D. C. Martinand, and R. Khokha. 1999. Timp-1 is important for epithelial proliferation and branching morphogenesis during mouse mammary development. Dev. Biol. 211:238-254.
Fata, J. E., A. T. V. Ho, K. J. Leco, R. A. Moorehead, and R. Khokha. 2000. Cellular turnover and extracellular matrix remodeling in female reproductive tissues: functions of metalloproteinases and their inhibitors. Cell. Mol. Life Sci. 57:77-95.
Faurchou, M., and N. Borregaard. 2003. Neutrophil granules and secretory vesicles in inflammation. Microbes Infect. 5:1317-1327.
Fleet, I. R., and M. Peaker. 1978. Mammary function and its control at the cessation in late lactation in goats. J. Physiol. 279:491-507.
Flint, D. J., M. Boutinaud, E. Tonner, C. J. Wilde, W. Hurley, P. A. Accorsi, A. F. Kolb, C. B. A. Whitelaw, J. Beattie, and G. J. Allan. 2005. Insulin-like growth factor binding proteins initiate cell death and extracellular matrix remodeling in the mammary gland. Domest. Anim. Endocrinol. 29:274-282.
Frodin, M., and S. Gammeltoft. 1999. Role and regulation of 90 kDa ribosomal S6 kinase (RSK) in signal transduction. Mol. Cell Endocrinol. 151:65-77.
Genersch, E., K. Hayess, Y. Neuenfeld, and H. Haller. 2000. Sustained ERK phosphorylation is necessary but not sufficient for MMP-9 regulation in endothelial cells: involvement of Ras dependent and–independent pathways. J. Cell Sci. 113:4319-4330.
Goetzl, E. J., M. J. Banda, and D. Leppert. 1996. Matrix metalloproteinases in immunity. J. Immunol. 165:1-4.
Goodman, R. E., and F. L. Schanbacher. 1991. Bovine lactoferrin mRNA: sequence, analysis, and expression in the mammary gland. Biochem. Biophys. Res. Commun. 180:75-84.
Granger, D. N., and P. Kubes. 1994. The microcirculation and inflammation: modulation of leukocyte-endothelial cell adhesion. J. Leukoc. Biol. 55:662-675.
Green, K. A., and L. R. Lund. 2005. ECM degrading proteases and tissue remodelling in the mammary gland. Bioassays. 27:894-903.
Grieve, P. A., and B. J. Kitchen. 1985. Proteolysis of milk: the significance of protease originating from milk leukocytes and a comparison of the action of leukocytes, bacterial and natural milk protease on casein. J. Dairy Res. 52:101-112.
Gross, J., and C. M. Lapiere. 1962. Collagenolytic activity in amphibian tissues: a tissue culture assay. Proc. Natl. Acad. Sci. USA. 47:1014-1022.
Gullberg, U., E. Andersson, D. Garwicz, A. Lindmark, and I. Olsson. 1997. Biosynthesis, processing and sorting of neutrophil proteins: insight into neutrophil granule development. Eur. J. Haematol. 58:137-153.
Harmon, R. J. 1994. Physiology of mastitis and factors affecting somatic cell counts. J. Dairy Sci. 77:2103-2112.
Haslam, S. Z. 1988. Cell to cell interactions and normal mammary gland function. J. Dairy Sci. 71:2843-2854.
Hayashi, M., R. R. Schellenberg, S. Tsang, and C. R. Roberts. 1999. Matrix metalloproteinase-9 in myeloid cells: Implications for allergic inflammation. Int. Arch. Allergy Immunol. 118:429-432.
Hirai, S., M. Izawa, S. Osada, G. Spyrou, and S. Ohno. 1996. Activation of the JNK pathway by distantly related protein kinases, MEKK and MUK. Oncogene. 12:641-650.
Hoeflich, K. P., and J. R. Woodgett. 2001. Signal transduction and gene expression in the regulation of natural freezing survival. Cell and Molecular Responses to Stress. 2:175-193.
Holst, B. D., W. L. Hurley, and D. R. Nelson. 1987. Involution of the bovine mammary gland: histological and ultrastructural changes. J. Dairy Sci. 70:935-944.
Holvoet, S., C. Vincent, D. Schmitt, and M. Serres. 2003. The inhibition of MAPK pathway is correlated with down-regulation of MMP-9 secretion induced by TNF-α in human keratinocytes. Exp. Cell Res. 290:108-119.
Hozumi, A., Y. Nishimura, T. Nishiuma, Y. Kotani, and M. Yokoyama. 2001. Induction of MMP-9 in normal human bronchial epithelial cells by TNFalpha via NF-kappa B-mediated pathway. Am. J. Physiol. Lung Cell Mol. Physiol. 281:L1444–L1452.
Hurley, W. L. 1989. Mammary gland function during involution. J. Dairy Sci. 72:1637-1646.
Hurley, W. L., M. Aslam, H. M. Hegarty, and A. Morkoc. 1994. Synthesis of lactoferrin and casein by explants of bovine mammary tissue. Cell Biol. Int. 18:629-637.
Hurley, W. L., and J. J. Rejman. 1993. Bovine lactoferrin in involuting mammary tissue. Cell Biol. Int. 17:283-289.
Ichijo, H., E. Nishida, K. Irie, P. Dijke, M. Saitoh, T. Moriguchi, M. Takagi, K. Matsumoto, K. Miyazono, Y. Gotoh. 1997. Induction of apoptosis by ASK1, a mammalian MAPKKK that activates SAPK/JNK and p38 signaling pathways. Science. 275:90-94.
Irving, E. A., and M. Bamford. 2002. Role of mitogen- and stress-activated kinases in ischemic injury. J. Cereb. Blood Flow Metab. 22:631-647.
Ito, A., A. Mukaiyama, Y. Itoh, H. Nagase, I. B. Thogersen, J. J. Enghild, Y. Sasaguri, and Y. Mori. 1996. Degradation of interleukin-1b by matrix metalloproteinases. J. Biol. Chem. 271:14657-14660.
Jensen, D. L., and R. J. Eberhart. 1981. Total and differential cell counts in secretions of the nonlactating bovine mammary gland. Am. J. Vet. Res. 42:743-747.
Johansson, N., M. Ahonen, and V. M. Kahari. 2000. Matrix metalloproteinases in tumor invasion. Cell. Mol. Life Sci. 57:5-15.
Kahari, V. M., and U. Saarialho-Kere. 1997. Matrix metalloproteinases in skin. Exp. Dermatol. 6:199-213.
Karin, M., Z. G. Liu, and E. Zandi 1997. AP-1 function and regulation. Curr. Opin. Cell Biol. 9:240-246.
Karin, M., and Delhase, M. 1998. JNK or IKK, AP-1 or NF-κB, which are the targets for MEKK1 action? Proc. Natl. Acad. Sci. USA. 95:9067-9069.
Kelly, A. L., S. Reid, P. Joyce, W. J. Meaney, and J. Foley. 1998. Effect of decreased milking frequency of cows in late lactation on somatic cell count, polymorphonuclear leukocyte numbers, composition and proteolytic activity. J. Dairy Res. 65:365-373.
Kelly, A. L., D. Tiernan, C. O''Sullivan, and P. Joyce. 2000. Correlation between bovine milk somatic cell count and polymorphonuclear leukocyte level for samples of bulk milk and milk from individual cows. J. Dairy Sci. 83:300-304.
Keyse, S. M. 2000. Protein phosphatases and the regulation of mitogen-activated protein kinase signalling. Curr. Opin. Cell Biol. 12:186-192.
Kirillova, I., M. Chaisson, and N. Fausto. 1999. Tumor necrosis factor induces DNA replication in hepatic cells through nuclear factor-κB activation. Cell Growth Differ. 10:819-828.
Kleifeld, O., P. E. Van den Steen, A. Frenkel, F. Cheng, H. L. Jiang, G. Opdenakker, and I. Sagi. 2000. Structural characterization of the catalytic active site in the latent and active natural gelatinase B from human neutrophils. J. Biol. Chem. 275:34335-34343.
Knight, C. H., D. Hirst, and R. J. Dewhurst. 1994. Milk accumulation and distribution in the bovine udder during the interval between milkings. J. Dairy Res. 61:167-177.
Kowanko, I. C., E. J. Bates, and A. Ferrante. 1989. Mechanisms of neutrophil- mediated cartilage damage in vitro: the role of lysosonal enzymes, hydrogen peroxide and hypochlorous acid. Immunol. Cell Biol. 67:321-329.
Kyriakis, J. M., and J. Avruch. 2001. Mammalian mitogen-activated protein kinase signal transduction pathways activated by stress and inflammation. Physiol. Rev. 81:807-869.
Lee, S. Y., A. Reichlin, A. Santana, K. A. Sokol, M. C. Nussenzweig, and Y. Choi. 1997. TRAF2 is essential for JNK but not NF-κB activation and regulates lymphocyte proliferation and survival. Immunity. 7:703-713.
Lefebvre, V., C. Peeters-Joris, and G. Vaes. 1991. Production of gelatin-degrading matrix metalloproteinases (type IV collagenases) and inhibitors by articular chondrocytes during their dedifferentiation by serial subcultures and under stimulation by interleukin-1 and tumor necrosis factor alpha. Biochim. Biophys. Acta. 1094:8-18.
Lewis, T. S., P. S. Shapiro, and N. G. Ahn. 1998. Signal transduction through MAP kinase cascades. Adv. Cancer Res. 74:49-139.
Lisovsky, M., K. Itoh, and S. Y. Sokol. 2002. Frizzled receptors activate a novel JNK-dependent pathway that may lead to apoptosis. Curr. Biol. 12:53-58.
Liu, Z., G. H. Hsu, D. V. Goeddel, and M. Karin. 1996. Dissection of TNF receptor 1 effector functions: JNK activation is not linked to apoptosis while NF-κB activation prevents cell death. Cell. 87:565-576.
Lokuta, M. A., and Huttenlocher. 2005. TNF-α promotes a stop signal that inhibit neutrophil polarization and migration via p38 MAPK pathway. J. Leukoc. Biol. 78:210-219.
Lowell, C. A., and G. Berton. 1999. Integrin signal transduction in myeloid leukocytes. J. Leukoc. Biol. 65:313-320.
Lund, L. R., J. Romer, N. Thomasset, H. Solberg, C. Pyke, M. J. Bissell, K. Dano, and Z. Werb. 1996. Two distinct phases of apoptosis in mammary gland involution: proteinase-independent and -dependent pathways. Development. 122:181-193.
Mainardi, C. L., M. S. Hibbs, K. A. Hasty, and J. M. Seyer. 1984. Purification of a type V collagen degrading metalloproteinase from rabbit alveolar macrophages. Coll. Relat. Res. 4:479-492.
Makowski, G. S., and M. L. Ramsby. 1996. Calibrating gelatin zymograms with human gelatinase standards. Anal. Biochem. 236:353-356.
Marom, B., M. A. Rahat, N. Lahat, L. Weiss-Cerem, A. Kinarty, and H. Bitterman. 2007. Native and fragmented fibronectin oppositely modulate monocyte secretion of MMP-9. J. Leukoc. Biol. 81:1-11.
Masure, S., P. Proost, J. Van Damme, and G. Opdenakker, 1991. Purification and identification of 91-kDa neutrophil gelatinase. Eur. J. Biochem. 198:391-398.
Mehrzad, J., C. Desrosiers, K. Lauzon, G. Robitaille, X. Zhao, and P. Lacasse. 2005. Protease involved in mammary tissue damage during endotoxin-induced mastitis in dairy cows. J. Dairy Sci. 88:211-222.
Miller, R. H., M. J. Paape, R. R. Peters, and M. D. Young. 1990. Total and differential somatic cell counts and N-acetyl-b-D-glucosaminidase activity in mammary secretions during dry period. J. Dairy Sci. 73:1751-1755.
Mitchell, G. E., S. A. Rogers, D. B. Houlihan, and V. C. Tucker. 1986. The relationship between somatic cell count, composition and manufacturing properties of bulk milk. 1. Composition of farm bulk milk. Aust. J. Dairy Tech. 41:9-12.
Moodie, S. A., and A. Wolfman. 1994. The 3Rs of life: Ras, Raf, and growth regulation. Trends Genet. 10:44-48.
Moreno, E., K. Basler, and G. Morata. 2002. Cell compete for decapentaplegic survival factor to prevent apoptosis in Drosophila wing development. Nature. 416:755-759.
Munro, G. L., P. A. Grieve, and B. J. Kitchen. 1984. Effects of mastitis on milk yield, milk composition, processing properties and yield and quality of milk products. Aust. J. Dairy Tech. 39:7-16.
Nagase, H., and J. F. Woessner Jr. 1999. Matrix metalloproteinases. J. Biol. Chem. 274:21491-21494.
Nagata, S. 1999. Fas ligand-induced apoptosis. Annu. Rev. Genet. 33:29-55.
Nakano, H., K. Kurosawa, S. Sakon, H. Yagita, W. C. Yeh, T. W. Mak, and K. Okumura. 2000. Impaired TNF-induced NF-κB activation and high sensitivity to TNF-induced cell death in TRAF2- and TRAF5-double deficient mice. Scand. J. Immunol. 51 (Suppl. 1) :71.
Oguma, K., R. Kano, and A. Hasegawa 2000. In vitro study of neutrophil apoptosis in dogs. Vet. Immunol. Immunopathol. 76:157-162.
Okada, Y., H. Tsuchiya, H. Shimizu, K. Tomita, I. Nakanishi, H. Sato, M. Seiki, K. Yamashita, and T. Hayakawa. 1990. Induction and stimulation of 92-kDa gelatinase/type IV collagenase production in osteosarcoma and fibrosarcoma cell lines by tumor necrosis factor alpha. Biochem. Biophys. Res. Commun. 171:610-617.
Olivier, S. P., and L. K. Smith. 1983. Bovine mammary involution following intramammary infusion of colchicine and endotoxin at drying-off. J. Dairy Sci. 65:801-813.
Ono, K., and J. Han. 2000. The p38 signal transduction pathway: activation and function. Cell Signal. 12:1-13.
Ontsouka, C. E., R. M. Bruckmaier, and J. M. Blum. 2003. Fractionized milk composition during removal of colostrum and mature milk. J. Dairy Sci. 86:2005-2011.
Oostveldt, V. K., F. Vangroenweghe, H. Dosogne, and C. Burvenich. 2001. Apoptosis and necrosis of blood and milk polymorphonuclear leukocytes in early and midlactating healthy cows. Vet. Res. 32:617-622.
Opdenakker, G., S. Masure, B. Grillet, and J. Van Damme. 1991. Cytokine-mediated regulation of human leukocyte gelatinases and role in arthritis. Lymphokine Cytokine Res. 10:317-324.
Opdenakker, G., P. E. Van den Steen, B. Dubois, I. Nelissen, E. V. Coillie, S. Masure, P. Proost, and J. V. Damme. 2001. Gelatinase B functions as regulator and effector in leukocyte biology. J. Leukoc. Biol. 69:851-859.
Opdenakker, G., and J. V. Damme. 1992. Chemotactic factors, passive invasion and metastasis of cancer cells. Immunol. Today. 13:463-464.
Orlowski, R. Z., and A. S. Baldwin. NF-kB as a therapeutic target in cancer. 2002. Trends Mol. Med. 8:385-389.
Overall, C. M. 1994. Regulation of tissue inhibitor of metalloproteinase expression. Ann. NY Acad. Sci. 732:51-63.
Overall, C. M. 2002. Molecular determinants of metalloproteinase substrate specificity: matrix metalloproteinase substrate binding domains, modules, and exosites. Mol. Biotechnol. 22:51-86.
Owen, C. A., and E. J. Campbell. 1999. The cell biology of leukocyte-mediated proteolysis. J. Leukoc. Biol. 65:137-150.
Paape, M. J., P. M. Rautiainen, E. M. Lilius, C. E. Malstrom, and T. H. Elsasser. 2002. Development of anti-bovine TNF-α mAb and ELISA for quantitating TNF-α in milk after intramammary injection of endotoxin J. Dairy Sci. 85:765-773.
Page-McCaw, A., A. J. Ewald, and Z. Werb. 2007. Matrix metalloproteinases and regulation of tissue remodeling. Nature. 8:221-233.
Park, H. I., J. Ni, F. E. Gerkema, D. Liu, V. E. Belozerov, and Q. X. Sang. 2000. Identification and characterization of human endometase (matrix metalloproteinase-26) from endometrial tumor. J. Biol. Chem. 275:20540-20544.
Park, Y. C., H. Ye, C. Hsia, D. Segal, R. L. Rich, H-C. Liou, D. G. Myszka, and H. Wu. 2000. A novel mechanism of TRAF signaling revealed by structural and functional analyses of the TRADD–TRAF2 interaction. Cell. 101:777-787.
Partridge, C. A., J. Jeffrey, and A. B. Malik. 1993. A 96 kDa gelatinase induced by TNF-alfa contributes to increased microvascular endothelial permeability. Am. J. Physiol. 265:438-447.
Pearson, G., F. Robinson, T. B. Gibson, B. E. Xu, M. Karandikar, K. Berman, and M. H. Cobb. 2001. Mitogen-activated protein (MAP) kinase pathways: regulation and physiological functions. Endocrinol. Rev. 22:153-183.
Pei, D., G. Majmudar, and S. J. Weiss. 1994. Hydrolytic inactivation of a breast carcinoma cell-derived serpin by human stromelysin-3. J. Biol. Chem. 269:25849-25855.
Peschon, J. J., J. L. Slack, P. Reddy, K. L. Stocking, S. W. Sunnarborg, D. C. Lee, W. E. Russell, B. J. Castner, R. S. Johnson, J. N. Fitzner, R. W. Boyce, N. Nelson, C. J. Kozlosky, M. W. Wolfson, C. T. Rauch, D. P. Cerretti, R. J. Paxton, C. J. March, and R. A. Black. 1998. An essential role for ectodomain shedding in mammalian development. Science. 282:1281-1284.
Philippe, E. V. S., B. Dubois, I. Nelissen, P. M. Rudd, R. A. Dwek, and G. Opdenakker. 2002. Biochemistry and molecular biology of gelatinase B or matrix metalloproteinase-9 (MMP-9). Crit. Rev. Biochem. Mol. Biol. 37:375-536.
Politis, I., E. Lachance, E. Block, and J. D. Turner. 1989. Plasmin and plasminogen in bovine milk: a relationship with involution. J. Dairy Sci. 72:900-906.
Pombo, C. M., J. V. Bonventre, J. Avruch, J. R. Woodgett, J. M. Kyriakis, and T. Force. 1994. The stress-activated protein kinases are major c-Jun amino-terminal kinases activated by ischemia and reperfusion. J. Biol. Chem. 269:26546-26551.
Pugin, J. M-C. W., S. Kossodo, C-M. Liang, H. L. Preas II, and A. F. Suffredini. 1999. Human neutrophils secrete gelatinase B in vitro and in vivo in response to endotoxin and proinflammatory mediators. Am. J. Respir. Cell Mol. Biol. 20:458-464.
Rabot, A., F. Sinowatz, B. Berisha, H. H. D. Meyer, and D. Schams. 2007. Expression and localization of extracellular matrix-degrading proteinases and their inhibitors in the bovine mammary gland during development, function, and involution. J. Dairy Sci. 90:740-748.
Ramso-DeSimone, N., E. Hahn-Dantona, J. Sipley, H. Nagase, D. L. French, and J. P. Quigley. 1999. Activation of matrix metalloproteinase-9 (MMP-9) via a converging plasmin/stromelysin-1 cascade enhances tumor cell invasion. J. Biol. Chem. 274:13066-13076.
Raulo, S. M., T. Sorsab, T. Tervahartialab, T. Latvanena, E. Piriläb, J. Hirvonena and P. Maisi. 2002. Increase in milk metalloproteinase activity and vascular permeability in bovine endotoxin-induced and naturally occurring Escherichia coli mastitis. Vet. Immunol. Immunopathol. 85:137-145.
Reddy, P., J. L. Slack, R. Davis, D. P. Cerretti, C. J. Kozlosky, R. A. Blanton, D. Shows, J. J. Peschon, and R. A. Black. 2000. Functional analysis of the domain structure of tumor necrosis factor-α converting enzyme. J. Biol. Chem. 275:14608-14614.
Rejman, J. J., W. L. Hurley, and J. M. Bahr. 1989. Enzyme-linked immunosorbent assay of bovine lactoferrin and a 39-kilodalton protein found in mammary secretions during involution. J. Dairy Sci. 72:555-560.
Remond, B., J. Rouel, N. Pinson, and S. Jabet. 1997. An attempt to omit the dry period over three consecutive lactations in dairy cows. Ann. Zootech. 46:399-408.
Richter, J., J. Ng-Sikorski, I. Olsson, and T. Andersson. 1990. Tumor necrosis factor-induced degranulation in adherent human neutrophils is dependent on CD11b/CD18-integrin-triggered oscillations of cytosolic free Ca2+. Proc. Natl. Acad. Sci. USA. 87:9472-9476.
Rivas, A. L., R. Tadevosyan, R. C. Gorewit, K. L. Anderson, R. Lyman, R. N. Gonzalez. 2006. Relationships between the phagocytic ability of milk macrophages and polymorphonuclear cells and somatic cell counts in uninfected cows. Can. J. Vet. Res. 70:68-74.
Robert, V., and H. Nagase. 2003. Matrix metalloproteinases and tissue inhibitors of metalloproteinases structure, function, and biochemistry. Circ. Res. 92:827-839.
Robinson, M. J., and M. H. Cobb. 1997. Mitogen-activated protein kinase pathways. Curr. Opin. Cell Biol. 9:180-186.
Robinson, S. C., K. A. Scott, and F. R. Balkwill. 2002. Chemokine stimulation of monocyte matrix metalloproteinase-9 requires endogenous TNF-α. Eur. J. Immunol. 32:404-412.
Rothe, M., M. Rothe, V. Sarma, V. M. Dixit, D. V. Goeddel. 1995. TRAF2-mediated activation of NF-κB by TNF receptor 2 and CD40. Science. 269:1424-1427.
Rothe, M. M. R., S. C. Wong, W. J. Henzel, and D. V. Goeddel. 1994. A novel family of putative signal transducers associated with the cytoplasmic domain of the 75 kDa tumor necrosis factor receptor. Cell. 78:681-692.
Roux, P. P., and Blenis, J. 2004. ERK and p38 MAPK-activated protein kinases: a family of protein kinases with diverse biological functions. Microbiol. Mol. Biol. Rev. 68:320-344.
Rudolph-Owen, L. A., and L. M. Matrisian. 1998. Matrix metalloproteinases in remodeling of the normal and neoplastic mammary gland. J. Mammary Gland Biol. Neoplasia. 3:177-189.
Saad, A. M., and K. Ostensson. 1990. Flow cytofluorometric studies on the alteration of leukocyte populations in blood and milk during endotoxin-induced mastitis in cows. Am. J. Vet. Res. 51:1603-1607.
Sanchez, L., M. Calvo, and J. H. Brock. 1992. Biological role of lactoferrin. Arch. Dis. Child. 67:657-661.
Saren, P., H. G. Welgus, and P. T. Kovanen. 1996. TNF-alpha and IL-1β selectively induce expression of 92-kDa gelatinase by human macrophages. J. Immunol. 157:4159-4165.
Schall, T. J., and K. B. Bacon. 1994. Chemokines, leukocyte trafficking, and inflammation. Curr. Opin. Immunol. 6:865-873.
Schlondorff, J., and C. P. Blobel. 1999. Metalloporotease-disintegrins: modular proteins capable of promoting cell-cell interactions and triggering signals by protein-ectodomain shedding. J. Cell Sci. 112:3603-3617.
Shamay, A., F. Shapiro, S. J. Mabjeesh, and N. Silanikove. 2002. Casein-derived phosphopeptides disrupt tight junction integrity, and precipitously dry up milk secretion in goats. Life Sci. 70:2707-2719.
Shamay, A., F. Shapiro, G. Leitner, and N. Silanikove. 2003. Infusions of casein hydrolyzates into the mammary gland disrupt tight junction integrity and induce involution in cows J. Dairy Sci. 86:1250-1258.
Shapiro, S. D., D. K. Kobayashi, and T. J. Ley. 1993. Cloning and characterization of a unique elastolytic metalloproteinase produced by human alveolar macrophages. J. Biol. Chem. 268:23824-23829.
Shapiro, S. D., and R. M. Senior. 1999. Matrix metalloproteinases. Matrix degradation and more. Am. J. Respir. Cell Mol. Biol. 20:1100-1102.
Shaulian, E., and M. Karin. 2002. AP-1 as a regulator of cell life and death. Nat. Cell Biol. 4:E131-E136.
Silberstein, G. B., and C. W. Daniel. 1982. Glycosaminoglycans in the basal lamina and extracellular matrix of the developing mouse mammary duct. Dev. Biol. 90:215-222.
Smith, R. A., and C. Baglioni. 1987. The active form of tumor necrosis factor is a trimer. J. Biol. Chem. 262:6951-6954.
Sopata, I., and A. M. Dancewics. 1974. Presence of gelatin-specific proteinase and its latent form in human leukocytes. Biochim. Biophys. Acta. 370:510-523.
Sordillo, L. M., and S. C. Nickerson. 1988. Morphologic changes in the bovine mammary gland during involution and lactogenesis. Am. J. Vet. Res. 49:1112-1120.
Stamenkovic, I. 2000. Matrix metalloproteinases in tumor invasion and metasis. Cancer Biol. 10:415-433.
Stanger, B. Z., P. Leder, T-H. Lee, E. Kim, and B. Seed. 1995. RIP: a novel protein containing a death domain that interacts with Fas/APO-1 (CD95) in yeast and causes cell death. Cell. 81:513-523.
Stangle, N. C., G. Kollias, and M. M. Ip. 1999. Disrupted mammary gland development in TNF knockout mice. Proc. Am. Assoc. Cancer Res. 40:161.
Stocker, W., F. Grams, U. Baumann, P. Reinemer, F-X. Gomis-Ruth, D. B. McKay, and W. Bode 1995. The metzincins-topological and sequential relations between the astacins, adamalysins, serralysins, and matrixins (collagenases) define a superfamily of zinc-peptidases. Protein Sci. 4:823-840.
Strongin, A. Y., I. Collier, G. Bannkiov, B. L. Marmer, G. A. Grant, and G. I. Goldberg. 1995. Mechanism of cell surface activation of 72-kDa type IV collagenase. J. Biol. Chem. 270:5331-5338.
Tak, P. P., and G. S. Firestein. 2001. NF-kB: a key role in inflammatory diseases. J. Clin. Invest. 107:7-11.
Talhouk, R. S., M. J. Bissell, and Z. Werb. 1992. Coordinated expression of extracellular matrix-degrading proteinases and their inhibitors regulates mammary epithelial function during involution. J. Cell Biol. 118:1271-1282.
Teramoto, H., P. Crespo, O. A. Coso, T. Igishi, N. Xu, and J. S. Gutkind. 1996. The small GTP binding protein RhoA activates c-Jun N-terminal kinase/stress-activated protein kinases in human kidney 293T cells. J. Biol. Chem. 271:25731-25734.
Trocmé, C., P. Gaudin, S. Berthier, C. Barro, P. Zaoui, and F. Morel. 1998. Human B lymphocytes synthesize the 92-kDa gelatinase, matrix metalloproteinase-9. J. Biol. Chem. 273:20677–20684.
Turner, J. D., and H. T. Huynh. 1991. Role of tissue remodeling in mammary epithelial cell proliferation and morphogenesis. J. Dairy Sci. 74:2801-2807.
Vaalamo, M., M-L. Karjalainen-Lindsberg, P. Puolakkainen , J. Kere, and U. K. Saarialho-Kere. 1998. Distinct expression profiles of stromelysin-2 (MMP-10), collagenase-3 (MMP-13), macrophage metalloelastase (MMP-12), and tissue inhibitor of metalloproteinases-3 (TIMP-3) in intestinal ulcerations. Am. J. Pathol. 152:1005-1014.
Van Wart, H. E., and H. Birkedal-Hansen. 1990. The cysteine switch: a principle of regulation of metalloproteinase activity with potential applicability to the entire matrix metalloproteinase gene family. Proc. Natl. Acad. Sci. USA. 87:5578-5582.
Vandenabeele, P., W. Declercq, R. Beyaert, and W. Fiers 1995. Two tumor necrosis factor receptors: structure and function. Trends Cell Biol. 5:392-399.
Varela, L. M., and M. M. Ip. 1996. Tumor necrosis factor-alpha: a multifunctional regulator of mammary gland development. Endocrinology. 137:4915-4924.
Varela, L. M., N. C. Stangle-Castor, S. F. Shoemaker, W. K. Shea-Eaton, and M. M. Ip. 2001. TNF induces NFkB/p50 in association with the growth and morphogenesis of normal and transformed rat mammary epithelial cells. J. Cell. Physiol. 188:120-131.
Varela, L. M., K. M. Darcy, and M. M. Ip. 2005. The epidermal growth factor receptor is not required for tumor necrosis factor-a action in normal mammary epithelial cells. Endocrinology. 138:3891-3900.
Visse, R., and H. Nagase. 2003. Matrix metalloproteinase and tissue inhibitors of metalloproteinase: structure, function, and biochemistry. Circ. Res. 92:827-839.
Walter, P., and G. Blobel. 1984. Protein translocation across the endoplasmic reticulum. Cell. 38:6-12.
Warburton, M. J., D. Mitchell, E. J. Ormerod, and P. Rudland. 1982. Distribution of myoepithelial cells and basement membrane proteins in resting, pregnant, lactating, and involuting rat mammary gland. J. Histochem. Cytochem. 30:667-676.
Weeks, B. S., H. W. Schnaper, M. Handy, E. Holloway, and H. K. Kleinman. 1993. Human T lymphocytes synthesize the 92 kDa type IV collagenase (gelatinase B). J. Cell Physiol. 157:644–649.
Whitmarsh, A. J., P. Shore, A. D. Sharrocks, and R. J. Devis. 1995. Integration of MAP kinase signal transduction pathways at the serum response element. Science. 269:403-407.
Wiehler, S., S. L. Cuvelier, S. Chakrabarti, and K. D. Patel. 2004. p38 MAP kinase regulates rapid matrix metalloproteinase-9 release from eosinophils. Biochem. Biophys. Res. Commun. 315:463-470.
Wilde, C. J., C. Addey, P. Li, and D. G. Fernig. 1997. Programmed cell death in bovine mammary tissue during lactation and involution. Exper. Physiol. 82:943-953.
Williams, J. M., and C. W. Daniel. 1983. Mammary ductal elongation: differentiation of myoepithelium and basal lamina during branching morphogenesis. Dev. Biol. 97:274-290.
Woessner, J. F. 1991. Matrix metalloproteinases and their inhibitors in connective tissue remodeling. FASEB J. 5:2145-2154.
Xia, Y. C. Makris, B. Su, E. Li, J. Yang, G. R. Nemerow, and M. Karin. 2000. MEK kinase 1 is critically required for c-Jun N-terminal kinase activation by proinflammatory stimuli and growth factor-induced cell migration. Proc. Natl. Acad. Sci. 97:5243-5248.
Xiao, Y. Q., K. Malcolm, G. S. Worthen, S. Gardai, W. P. Schiemann, V. A. Fadok, D. L. Bratton, and P. M. Henson. 2002. Cross-talk between ERK and p38 MAPK mediates selective suppression of pro-inflammatory cytokines by transforming growth factor-β. J. Biol. Chem. 277:14884-14893.
Yeh, W. C., J. L. Pompa, M. E. McCurrach, H-B. Shu, A. J. Elia, A. Shahinian, M. Ng, A. Wakeham, W. Khoo, K. Mitchell, W. S. El-Deiry, S. W. Lowe, D. V. Goeddel, and T. W. Mak. 1998. FADD: essential for embryo development and signaling from some, but not all, inducers of apoptosis. Science. 279:1954-1958.
Yujiri, T., M. Ware, C. Widmann, R. Oyer, D. Russell, E. Chan, Y. Zaitsu, P. Clarke, K. Tyler, Y. Oka, G. R. Fanger, P. Henson, and G. L. Johnson. 2000. MEKK1 gene disruption alters cell migration and c-Jun NH2-terminal kinase regulation but does not cause a measurable defect in NF-κB activation. Proc. Natl. Acad. Sci. USA. 97:7272-7277.
Zhang, Y., L. Zhou, and C. A. Miller. 1998. A splicing variant of a death domain protein that is regulated by mitogen-activated kinase is a substrate for c-Jun N-terminal kinase in the human central nervous system. Proc. Natl. Acad. Sci. USA. 95:2586-2591.
Zhu, X., B. Jacobs, E. Boetticher, S. Myou, A. Meliton, H. Sano, A. T. Lambertino, N. M. Munoz, and A. R. Leff. 2002. IL-5-induced integrin adhesion of human eosinophils caused by ERK1/2-mediated activation of cPLA2. J. Leukoc. Biol. 72:1046-1053.
Zu, Y. L., J. Qi, A. Gilchrist, G. A. Fernandez, D. Vazquez-Abad, D. L. Kreutzer, C. K. Huang, and R. I. Sha''afi. 1998. p38 mitogen-activated protein kinase activation is required for human neutrophil function triggered by TNF- or FMLP stimulation. J. Immunol. 1998:1982-1989.