- Email: [email protected]
Role of Extracellular Matrices, Matrix Receptors, and Cytokines in Granulomatous Lung Inflammation
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and VCAM-l and in homotypic cell clustering. J Cell Bioi 1992; 117:179-89 Holzmann B, McIntyre B\v, ~issman IL. Identification of a murine Peyers patch-specific lymphocyte homing receptor as an integrin molecule with an aIpha chain homologous to human VLA-4aIpha. Cell 1989; 56:37-46 Holzmann B, ~issman IL. Peyer's patch-speciflc lymphocyte homing receptors consist of a VLA-4-like alphachainassociated with either of two integrin beta chains, one of which is novel. Embo J 1989; 8:1735-41 Holzmann B, ~issman IL. Integrin molecules involved in lymphocyte homing to Peyer's patches. Immunol Rev 1989; 108:45-61 Lasky LA, Singer MS, Dowbenko D, et aI. An endothelial ligand for L-selectin is a novel mucin-like molecule. Cell 1992:
69:927-38 120 Streeter PR, lien B, Rouse N, et aI. Immunohistologic and functional characterization of a vascular addressin involved in lymphocyte homing into peripberallymph nodules. J Cell Bioi 1988: 107:1853-62 121 Imai Y, Singer MS, Fennie C, et aI. Identification of a carbohydrate-based endothelial ligand for a lymphocyte homing receptor. J Cell Bioi 1991: 113:1213-21 122 Streeter PR, Berg EL, Rouse BT, -et al, A tissue-specific endothelial cell molecule involved in lymphocyte homing. Nature 1988; 331:41-6 123 Nalcache M, Berg EL, Streeter PR, et aI. The mucosal vascular addressin is a tissue-specific endothelial cell adhesion molecule for circulating lymphocytes. Nature 1989: 337:179-81 124 Dailey MO, Fathman CG, Butcher EC, et aI. Abnormal migration ofT lymphocyte clones. J Immunoll982: 128:213436
125 Dailey MO, Gallatin WM, Kraal G, et aI. T cell clones: a model of a nonrecirculating phase of T cell differentiation. Adv Exp
Characterization of the Leukocyte Integrln Subunit P7*
Curzio Riiegg, M.D.; Robert Pytela, Ph.D.; and David] Erie, M.D .
M
embers of the integrin family of adhesion molecules mediate both cell-cell and cell-extracelluJar matrix interactions. We and others recently identified cDNAs encoding a novel integrin ~ subunit, ~7, in lymphocytes. We now show that ~7 protein and mRNA are expressed primarily or exclusivelyin mononuclear leukocytes. The ~7 containing integrins are present on some leukocytes in a wide range of organs, including the lung. The ~7 mRNA levels increase markedly after stimulation of peripheral blood T cells (with OKT3) or monocytes (with LPS, TNF, ILl, or IFN-"(). ~7 can associate with the ex4 subunit and with at least 1 other ex subunit. ex4~7 is apparently identical to ex4~P (LPAM-I), a molecule previously shown to playa role in binding to Peyers patch high endothelial venules. We studied the function of ex4~7 in TK-I murine lymphoma cells, which do not express VLA-4 (ex4~1). Binding of TK-I cells to fibronectin was completely inhibited by antibodies to ex4. We showed that ex4~7 binds to the CS-I region of fibronectin using affinity chromatography. TK-I -From the Lung Biology Center, University of California, San Francisco.
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Med Bioi 1985; 186:621-27 126 Jung TM, Gallatin WM, ~issman IL , et aI. Down-regulation of homing receptors after T cell activation. J Immunol 1988: 141:4110-17 127 Cush 11, Lipsky PE . Phenotypic analysis of synovial tissue and peripheral blood lymphocytes isolated from patients with rheumatoid arthritis. Arthritis Rheum 1988; 31:1230-38 128 Shimizu Y, Newman \v, Gopal Tv, et al. Four molecular pathways ofT cell adhesion to endothelial cells : roles of LFAI, VCAM-l, and ELAM-l and changes in pathway hierarchy under different activation conditions. J Cell Bioi 1991 ; 113:1203-12 129 Sanders ME, Makgoba M\v, Sharrow SO, et aI. Human memory T lymphocytes express increased levels of three cell adhesion molecules (LFA-3, CD2, and LFA-l) and three other molecules (UCHL1, CDw29, and Pgp-l) and have enhanced IFN-gamma production. J Immunoll988: 140:1401..{)7 130 Shimizu Y, van Seventer GA, Horgan KJ, et aI. Regulated expression and binding of three VLA (beta 1) integrin receptors on T cells. Nature 1990: 345:250-53 131 Kilshaw PJ, Murant SJ. Expression and regulation of beta 7 (beta p) integrins on mouse lymphocytes: relevance to the mucosal immune system. Eur J Immunoll991; 21:2591-97 132 Yuan Q, Jiang WM, Leung E, et aI. Molecular cloning of the mouse integrin beta 7 subunit. J Bioi Chem 1992: 267:7352-58 133 Cerf-Bensussan N, Begue B, Gagnon J, et aI. The human intraepitheliallymphocyte marker HML-l is an integrin consisting of a beta 7 subunit associated with a distinctive aIpha chain. Eur J Immunoll992: 22:273-77 134 Berg M, Muralcawa Y, Camerini D , et aI. Lamina propria lymphocytes are derived from circulating cells that lack the Leu-8 lymph node homing receptor. Gastroenterology 1991; 101:90-9
cell adhesion to VCAM-I was also inhibited by antibodies to ex4, implying that ex4~7 can also mediate adherence of leukocytes to endothelial cells by binding to VCAM-1. ex4~7 mediated adherence to fibronectin and VCAM-I is markedly increased by brief PMA stimulation. We also found that monoclonal antibodies against ex4 and ~7 induce homotypic clustering ofTK-1 cells, suggesting that ex4~7 might playa role in lymphocyte-lymphocyte interactions. We conclude that the leukocyte integrin ex4~7/ex4~P is a receptor for fibronectin and VCAM-I and that its role is unlikely to be restricted to lymphocyte homing.
Role of Extracellular Matrices, Matrix Receptors, and Cytokines in Granulomatous Lung Inflammatlon* Rafael L. ftmlz, M.D., EC .C.P.; Young-June Jeon, M.D., EC.C.P.; Gerald W Staton Jr., M.D., EC .C.P.; and Jesse Roman, M.D.
for granuloma formation in the lung are T henotmechanisms well understood. Although activated mononuclear cells seem critical for granuloma formation, the factors that regulate their function remain largely unknown. We propose
-From Emory University School of Medicine and the Veterans Affairs MedicaI Center, Atlanta.
that extracellular matrices (ECMs), proinBammatory cytokines, and cells interact in a way that leads to granuloma structure and function. In support of this proposition, we observed increased deposition of the ECM component fibronectin (FN), the FN integrin receptor, aSfH, and transforming growthfactor-B immunohistochemicallyin lung sections from patients with pulmonary sarcoidosis, a systemic illness characterized by granulomatous inflammation. We extended these observations to a murine model of lung granulomatous inflammation induced by the intravenous injection of the mycobacterial cord factor trehalose-6,6'dimycolate (TOM). Treabnent with TOM results in the formation of multiple pulmonary granulomas which peak in number 2 to 5 days after TOM injection and subside thereafter. The pulmonary histopathology of TOM-treated mice is associated with a marked increase in lung weight and alveolar exudate by bronchoalveolar lavage (BAL). The BAL neutrophils are prominent early in granuloma formation and are replaced by lymphocytes during the latter stages of granuloma formation. As in the sarcoidosis specimens, we found FN deposition within and around the TOM
granulomas. Granuloma-associated cells, as well as free cells in surrounding alveoli, expressed a5~1 suggesting that FN receptor-armed cells are able to interact with granuloma FN. The distribution of transforming growth factor-B. which has been shown to increase the expression of FN and the FN receptor in vitro, was similar to a5~1. Initial studies to determine the mechanisms by which TDM induces granuloma formation showed that TDM rapidly induced the expression of tumor necrosis factor-a, a multipotential monokine thought to be important in granuloma initiation, by murine peritoneal cells and human peripheral blood mononuclear cells. Our observations suggest that TOM-induced granulomatous inflammation is associated with the activation of mononuclear cells and their production of proinflammatory cytokines. These cytokines, among other things, may stimulate ECM deposition which, in tum, may affect the behavior of inflammatory cells armed with matrix receptors. Granuloma formation, resolution, and/or progression is likely to be determined by the consequences of these complex interactions.
CHEST I 103 I 3 I FEBRUARY, 1993 I Supplement
87S
117
118
119
and VCAM-l and in homotypic cell clustering. J Cell Bioi 1992; 117:179-89 Holzmann B, McIntyre B\v, ~issman IL. Identification of a murine Peyers patch-specific lymphocyte homing receptor as an integrin molecule with an aIpha chain homologous to human VLA-4aIpha. Cell 1989; 56:37-46 Holzmann B, ~issman IL. Peyer's patch-speciflc lymphocyte homing receptors consist of a VLA-4-like alphachainassociated with either of two integrin beta chains, one of which is novel. Embo J 1989; 8:1735-41 Holzmann B, ~issman IL. Integrin molecules involved in lymphocyte homing to Peyer's patches. Immunol Rev 1989; 108:45-61 Lasky LA, Singer MS, Dowbenko D, et aI. An endothelial ligand for L-selectin is a novel mucin-like molecule. Cell 1992:
69:927-38 120 Streeter PR, lien B, Rouse N, et aI. Immunohistologic and functional characterization of a vascular addressin involved in lymphocyte homing into peripberallymph nodules. J Cell Bioi 1988: 107:1853-62 121 Imai Y, Singer MS, Fennie C, et aI. Identification of a carbohydrate-based endothelial ligand for a lymphocyte homing receptor. J Cell Bioi 1991: 113:1213-21 122 Streeter PR, Berg EL, Rouse BT, -et al, A tissue-specific endothelial cell molecule involved in lymphocyte homing. Nature 1988; 331:41-6 123 Nalcache M, Berg EL, Streeter PR, et aI. The mucosal vascular addressin is a tissue-specific endothelial cell adhesion molecule for circulating lymphocytes. Nature 1989: 337:179-81 124 Dailey MO, Fathman CG, Butcher EC, et aI. Abnormal migration ofT lymphocyte clones. J Immunoll982: 128:213436
125 Dailey MO, Gallatin WM, Kraal G, et aI. T cell clones: a model of a nonrecirculating phase of T cell differentiation. Adv Exp
Characterization of the Leukocyte Integrln Subunit P7*
Curzio Riiegg, M.D.; Robert Pytela, Ph.D.; and David] Erie, M.D .
M
embers of the integrin family of adhesion molecules mediate both cell-cell and cell-extracelluJar matrix interactions. We and others recently identified cDNAs encoding a novel integrin ~ subunit, ~7, in lymphocytes. We now show that ~7 protein and mRNA are expressed primarily or exclusivelyin mononuclear leukocytes. The ~7 containing integrins are present on some leukocytes in a wide range of organs, including the lung. The ~7 mRNA levels increase markedly after stimulation of peripheral blood T cells (with OKT3) or monocytes (with LPS, TNF, ILl, or IFN-"(). ~7 can associate with the ex4 subunit and with at least 1 other ex subunit. ex4~7 is apparently identical to ex4~P (LPAM-I), a molecule previously shown to playa role in binding to Peyers patch high endothelial venules. We studied the function of ex4~7 in TK-I murine lymphoma cells, which do not express VLA-4 (ex4~1). Binding of TK-I cells to fibronectin was completely inhibited by antibodies to ex4. We showed that ex4~7 binds to the CS-I region of fibronectin using affinity chromatography. TK-I -From the Lung Biology Center, University of California, San Francisco.
88S
Med Bioi 1985; 186:621-27 126 Jung TM, Gallatin WM, ~issman IL , et aI. Down-regulation of homing receptors after T cell activation. J Immunol 1988: 141:4110-17 127 Cush 11, Lipsky PE . Phenotypic analysis of synovial tissue and peripheral blood lymphocytes isolated from patients with rheumatoid arthritis. Arthritis Rheum 1988; 31:1230-38 128 Shimizu Y, Newman \v, Gopal Tv, et al. Four molecular pathways ofT cell adhesion to endothelial cells : roles of LFAI, VCAM-l, and ELAM-l and changes in pathway hierarchy under different activation conditions. J Cell Bioi 1991 ; 113:1203-12 129 Sanders ME, Makgoba M\v, Sharrow SO, et aI. Human memory T lymphocytes express increased levels of three cell adhesion molecules (LFA-3, CD2, and LFA-l) and three other molecules (UCHL1, CDw29, and Pgp-l) and have enhanced IFN-gamma production. J Immunoll988: 140:1401..{)7 130 Shimizu Y, van Seventer GA, Horgan KJ, et aI. Regulated expression and binding of three VLA (beta 1) integrin receptors on T cells. Nature 1990: 345:250-53 131 Kilshaw PJ, Murant SJ. Expression and regulation of beta 7 (beta p) integrins on mouse lymphocytes: relevance to the mucosal immune system. Eur J Immunoll991; 21:2591-97 132 Yuan Q, Jiang WM, Leung E, et aI. Molecular cloning of the mouse integrin beta 7 subunit. J Bioi Chem 1992: 267:7352-58 133 Cerf-Bensussan N, Begue B, Gagnon J, et aI. The human intraepitheliallymphocyte marker HML-l is an integrin consisting of a beta 7 subunit associated with a distinctive aIpha chain. Eur J Immunoll992: 22:273-77 134 Berg M, Muralcawa Y, Camerini D , et aI. Lamina propria lymphocytes are derived from circulating cells that lack the Leu-8 lymph node homing receptor. Gastroenterology 1991; 101:90-9
cell adhesion to VCAM-I was also inhibited by antibodies to ex4, implying that ex4~7 can also mediate adherence of leukocytes to endothelial cells by binding to VCAM-1. ex4~7 mediated adherence to fibronectin and VCAM-I is markedly increased by brief PMA stimulation. We also found that monoclonal antibodies against ex4 and ~7 induce homotypic clustering ofTK-1 cells, suggesting that ex4~7 might playa role in lymphocyte-lymphocyte interactions. We conclude that the leukocyte integrin ex4~7/ex4~P is a receptor for fibronectin and VCAM-I and that its role is unlikely to be restricted to lymphocyte homing.
Role of Extracellular Matrices, Matrix Receptors, and Cytokines in Granulomatous Lung Inflammatlon* Rafael L. ftmlz, M.D., EC .C.P.; Young-June Jeon, M.D., EC.C.P.; Gerald W Staton Jr., M.D., EC .C.P.; and Jesse Roman, M.D.
for granuloma formation in the lung are T henotmechanisms well understood. Although activated mononuclear cells seem critical for granuloma formation, the factors that regulate their function remain largely unknown. We propose
-From Emory University School of Medicine and the Veterans Affairs MedicaI Center, Atlanta.
that extracellular matrices (ECMs), proinBammatory cytokines, and cells interact in a way that leads to granuloma structure and function. In support of this proposition, we observed increased deposition of the ECM component fibronectin (FN), the FN integrin receptor, aSfH, and transforming growthfactor-B immunohistochemicallyin lung sections from patients with pulmonary sarcoidosis, a systemic illness characterized by granulomatous inflammation. We extended these observations to a murine model of lung granulomatous inflammation induced by the intravenous injection of the mycobacterial cord factor trehalose-6,6'dimycolate (TOM). Treabnent with TOM results in the formation of multiple pulmonary granulomas which peak in number 2 to 5 days after TOM injection and subside thereafter. The pulmonary histopathology of TOM-treated mice is associated with a marked increase in lung weight and alveolar exudate by bronchoalveolar lavage (BAL). The BAL neutrophils are prominent early in granuloma formation and are replaced by lymphocytes during the latter stages of granuloma formation. As in the sarcoidosis specimens, we found FN deposition within and around the TOM
granulomas. Granuloma-associated cells, as well as free cells in surrounding alveoli, expressed a5~1 suggesting that FN receptor-armed cells are able to interact with granuloma FN. The distribution of transforming growth factor-B. which has been shown to increase the expression of FN and the FN receptor in vitro, was similar to a5~1. Initial studies to determine the mechanisms by which TDM induces granuloma formation showed that TDM rapidly induced the expression of tumor necrosis factor-a, a multipotential monokine thought to be important in granuloma initiation, by murine peritoneal cells and human peripheral blood mononuclear cells. Our observations suggest that TOM-induced granulomatous inflammation is associated with the activation of mononuclear cells and their production of proinflammatory cytokines. These cytokines, among other things, may stimulate ECM deposition which, in tum, may affect the behavior of inflammatory cells armed with matrix receptors. Granuloma formation, resolution, and/or progression is likely to be determined by the consequences of these complex interactions.
CHEST I 103 I 3 I FEBRUARY, 1993 I Supplement
87S