Integrin-mediated Tyrosine Phosphorylation and Cytokine Message Induction in Monocytic Cells

Activation of cytoplasmic tyrosine kinases is an important aspect of signal transduction mediated by integrins. In the human monocytic cell line THP-1, either integrin-dependent cell adhesion to fibronectin or ligation of β1 integrins with antibodies causes a rapid and intense tyrosine phosphorylation of two sets of proteins of about 65-75 and 120-125 kDa. In addition, integrin ligation leads to nuclear translocation of the p50 and p65 subunits of the NF-κB transcription factor, to activation of a reporter gene driven by a promoter containing NF-κB sites, and to increased levels of mRNAs for immediate-early genes, including the cytokine interleukin (IL)-1β. The tyrosine kinase inhibitors genistein and herbimycin A block both integrin-mediated tyrosine phosphorylation and increases in IL-1β message levels, indicating a causal relationship between the two events. The components tyrosine phosphorylated subsequent to cell adhesion include paxillin, pp125FAK, and the SH2 domain containing tyrosine kinase Syk. In contrast, integrin ligation with antibodies induces tyrosine phosphorylation of Syk but not of FAK or paxillin. In adhering cells, pre-treatment with cytochalasin D suppresses tyrosine phosphorylation of FAK and paxillin but not of Syk, while IL-1β message induction is unaffected. These observations indicate that the Syk tyrosine kinase may be an important component of an integrin signaling pathway in monocytic cells, leading to activation of NF-κB and to increased levels of cytokine messages. Activation of cytoplasmic tyrosine kinases is an important aspect of signal transduction mediated by integrins. In the human monocytic cell line THP-1, either integrin-dependent cell adhesion to fibronectin or ligation of β1 integrins with antibodies causes a rapid and intense tyrosine phosphorylation of two sets of proteins of about 65-75 and 120-125 kDa. In addition, integrin ligation leads to nuclear translocation of the p50 and p65 subunits of the NF-κB transcription factor, to activation of a reporter gene driven by a promoter containing NF-κB sites, and to increased levels of mRNAs for immediate-early genes, including the cytokine interleukin (IL)-1β. The tyrosine kinase inhibitors genistein and herbimycin A block both integrin-mediated tyrosine phosphorylation and increases in IL-1β message levels, indicating a causal relationship between the two events. The components tyrosine phosphorylated subsequent to cell adhesion include paxillin, pp125FAK, and the SH2 domain containing tyrosine kinase Syk. In contrast, integrin ligation with antibodies induces tyrosine phosphorylation of Syk but not of FAK or paxillin. In adhering cells, pre-treatment with cytochalasin D suppresses tyrosine phosphorylation of FAK and paxillin but not of Syk, while IL-1β message induction is unaffected. These observations indicate that the Syk tyrosine kinase may be an important component of an integrin signaling pathway in monocytic cells, leading to activation of NF-κB and to increased levels of cytokine messages. Members of the integrin family of cell surface receptors are involved in many key biological processes, including cell to cell and cell to extracellular matrix adhesion, cell motility, hemostasis, lymphocyte trafficking, and inflammatory phenomena(1Bevilacqua M.P. Annu. Rev. Immunol. 1993; 11: 767-804Crossref PubMed Scopus (1254) Google Scholar, 2Hemler M.E. Ann. Rev. Immunol. 1990; 8: 365-400Crossref PubMed Google Scholar, 3Ginsberg M.H. Xiaoping D. O'Toole T.E. Loftus J.C. Plow E.F. Thromb. 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In fibroblasts, platelets, endothelial cells, and cultured tumor cells, integrin-induced tyrosine phosphorylation involves a novel cytoplasmic tyrosine kinase termed pp125 focal adhesion kinase (pp125FAK)1( 1The abbreviations are: FAKfocal adhesion kinaseBSAbovine serum albuminECMextracellular matrixILinterleukinPAGEpolyacrylamide gel electrophoresisPBSphosphate-buffered salineCATchloramphenicol acetyltransferaseEMSAelectrophoretic mobility shift assay. 1The abbreviations are: FAKfocal adhesion kinaseBSAbovine serum albuminECMextracellular matrixILinterleukinPAGEpolyacrylamide gel electrophoresisPBSphosphate-buffered salineCATchloramphenicol acetyltransferaseEMSAelectrophoretic mobility shift assay.)(6Hanks S.K. Calalb M.B. Harper M.C. Patel S.K. Proc. Natl. Acad. Sci. U. S. A. 1992; 89: 8487-8491Crossref PubMed Scopus (730) Google Scholar, 7Sinnett-Smith J. Zachary I. Valverde A.M. Rozengurt E. J. Biol. 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Integrins are prominent among the cell surface receptors that mediate many of the adhesive functions of monocytes(1Bevilacqua M.P. Annu. Rev. Immunol. 1993; 11: 767-804Crossref PubMed Scopus (1254) Google Scholar, 2Hemler M.E. Ann. Rev. Immunol. 1990; 8: 365-400Crossref PubMed Google Scholar). In human peripheral blood monocytes, cell adherence to ECM components or ligation of β1 integrins with antibodies results in the rapid induction of multiple inflammatory mediator genes including several cytokines(18Haskill S. Johnson C. Eierman D. Becker S. Warren K. J. Immunol. 1988; 140: 1690-1694PubMed Google Scholar, 19Haskill S. Beg A.A. Tompkins S.M. Morris J.S. Yurochko A.D. Sampson-Johannes A. Mondal K. Ralph P. Baldwin Jr., A.S. Cell. 1991; 65: 1281-1289Abstract Full Text PDF PubMed Scopus (586) Google Scholar, 20Yurochko A.D. Liu D.Y. Eierman D. Haskill S. Proc. Natl. Acad. Sci. U. S. A. 1992; 89: 9034-9038Crossref PubMed Scopus (197) Google Scholar). The 5′-regulatory regions of many of the genes induced by integrin ligation contain binding motifs for the NF-κB transcription factor, suggesting a role for this factor in the gene induction process(5Juliano R.L. Haskill S. J. Cell Biol. 1993; 120: 577-585Crossref PubMed Scopus (1538) Google Scholar). In parallel to gene induction, a rapid and profound increase in protein tyrosine phosphorylation is observed, with the predominant phosphorylated component(s) having a molecular mass of about 76 kDa(21Lin T.H. Yurochko A. Kornberg L. Morris J. Walker Haskill S. Juliano R.L. J. Cell Biol. PubMed Scopus Google Scholar). of these are by tyrosine kinase suggesting an important role for protein tyrosine phosphorylation in integrin signaling leading to inflammatory mediator gene tyrosine is of integrin-mediated signal transduction in monocytic cells. A for this is the involved in biochemical or molecular peripheral blood monocytes as well as the to with these cells. In this a cell the human monocytic cell THP-1, which important aspects of to ECM cell adhesion to ECM proteins or ligation of β1 integrins with induces protein tyrosine increases inflammatory mediator gene message levels, and the NF-κB transcription These are by tyrosine kinase inhibitors as herbimycin A and the proteins tyrosine phosphorylated in cells in to cell adhesion to ECM components are the S.K. Calalb M.B. Harper M.C. Patel S.K. Proc. Natl. Acad. Sci. U. S. A. 1992; 89: 8487-8491Crossref PubMed Scopus (730) Google Scholar, M.D. Parsons J.T. Cell Biol. 1993; Full Text PDF PubMed Scopus Google Scholar), the focal protein K. J. Cell Biol. 1992; PubMed Scopus Google Scholar), and the tyrosine kinase J. K. J. K. J. Biol. Chem. 1991; Full Text PDF PubMed Google Scholar, A. S. J. Biol. Chem. Full Text PDF PubMed Google Scholar). of β1 integrins with intact antibodies or with results in the tyrosine phosphorylation of Syk but not of FAK or paxillin. 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A. 1992; 89: 9034-9038Crossref PubMed Scopus (197) Google and a with The with the in and and with and The by the to the of integrins the cell surface by cells in several integrin subunits including and not also these cells to ECM in cells to tissue with or cells the of cell adhesion to the fibronectin a of adherence to and levels of cell adhesion to or while only a cells to cell adhesion to fibronectin mediated by cells with or with a the β1 integrin that both and integrin cell adhesion to with or These results indicate that cells β1 integrins to interact with and to ECM components as cells for of cells for protein phosphorylation tyrosine by in cell adhesion to fibronectin to a increase in tyrosine phosphorylation of several including and kDa. The increase in tyrosine phosphorylation cells to the fibronectin a and then but Cell adhesion to fibronectin also induced increased message levels of the inflammatory mediator gene that induction of IL-1β message cell adhesion to fibronectin the it can be that the induction of tyrosine phosphorylation to IL-1β message The increase in IL-1β message levels have that other cytokine are also increased adhesion to fibronectin not ligation of integrins has been to the integrin that of adhesive L. Parsons J.T. M. Juliano R.L. J. Biol. 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The of inhibitors to block Syk activation to to the of tyrosine phosphorylation and the induction of IL-1β in monocytic cells, Syk is an tyrosine kinase activation and may the induction of cytokine of and integrin Syk kinase by herbimycin A or cells with herbimycin A or genistein as in Syk kinase cell and for as In parallel with the kinase the of Syk kinase in the by herbimycin have the role of the in the induction of tyrosine phosphorylation and IL-1β message by of the cytochalasin an of G. J. 1992; PubMed Google Scholar). in with cytochalasin D of cells fibronectin but not The tyrosine phosphorylation of and of paxillin, that is induced in cells by with a fibronectin is by cytochalasin D that of is for these phosphorylation events. contrast, tyrosine phosphorylation of Syk is not by cytochalasin D IL-1β message induction is not These observations between integrin signaling events that and events as Syk activation that not have this also indicate that is not for integrin-mediated increases in IL-1β message of β1 integrins in peripheral blood monocytes results in a and induction of a of inflammatory mediator genes including and tumor factor, as well as genes for a of transcription factors Recently, have that β1 integrin ligation in monocytes also results in a of tyrosine phosphorylation and that this is for subsequent integrin-mediated gene T.H. Yurochko A. Kornberg L. Morris J. Walker Haskill S. Juliano R.L. J. Cell Biol. PubMed Scopus Google Scholar). have that including integrin-mediated tyrosine phosphorylation and increases in inflammatory gene message levels, also in cells, a monocytic cell line that is to of biochemical and molecular events are also that the transcription factor NF-κB is in to integrin have of the proteins that are tyrosine phosphorylated in cells subsequent to integrin these include the focal protein paxillin and the FAK and Syk tyrosine kinases. The of tyrosine phosphorylation induced in cells by integrin-mediated cell adhesion or by ligation of β1 integrins are but types of in prominent tyrosine phosphorylation of several components in the and the However, as in cell integrin-mediated adhesion to fibronectin a 65-75 while ligation results in phosphorylation of the molecular mass component of the among the proteins adhesion results in phosphorylation of a component while ligation a component The for the in tyrosine phosphorylation in cells by antibodies and by integrin-mediated cell adhesion is this One is that cell adhesion results in a of the the of integrin or by antibodies and the of can the of proteins to tyrosine in the of tyrosine phosphorylation induced by cell adhesion or by ligation of it is that both of these can NF-κB and can to increased levels of cytokine messages. as have for cells and for T.H. Yurochko A. Kornberg L. Morris J. Walker Haskill S. Juliano R.L. J. Cell Biol. PubMed Scopus Google Scholar), inhibitors of tyrosine kinases can block message induction mediated by cell adhesion or by ligation of β1 integrins. These inhibitors also activation of an NF-κB driven in not it that integrin can activation of tyrosine kinases and protein tyrosine phosphorylation events that are for the of inflammatory mediator genes in monocytic cells. it is important to integrin-mediated tyrosine phosphorylation to to events to the message induction have for of integrin-mediated tyrosine phosphorylation of several proteins as involved in signal transduction or linked to integrin-dependent In cells, the focal protein paxillin and the cytoplasmic tyrosine kinases FAK and Syk tyrosine phosphorylated in to integrin-mediated cell The activation of FAK by integrin as well as by other has been in a of cell L. Parsons J.T. M. Juliano R.L. J. Biol. Chem. 1992; Full Text PDF PubMed Google Scholar, L. M.D. Cobb B.S. Parsons J.T. J.S. J. 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These results may have underlying to the results of receptors may of the the for FAK and paxillin integrin-mediated cell adhesion or ligation of integrins can increase IL-1β message levels, as well as changes in protein tyrosine However, ligation the Syk tyrosine kinase but not FAK or paxillin. with cytochalasin which cell and FAK and paxillin tyrosine to block Syk tyrosine phosphorylation or increases in IL-1β message it that FAK is not for integrin-mediated IL-1β message induction in cells, with observations T.H. Yurochko A. Kornberg L. Morris J. Walker Haskill S. Juliano R.L. J. Cell Biol. PubMed Scopus Google Scholar). results that Syk may an important role in the signal transduction leading integrin to the induction of inflammatory mediator the activation of Syk and integrin-mediated gene induction, while of tyrosine kinase inhibitors block both Syk and IL-1β message The integrin-mediated changes in tyrosine phosphorylation and Syk activation are cell adhesion or that these are through the of protein that are induced or subsequent to integrin events have been with the of kinase by D. PubMed Scopus Google Scholar). that Syk is an tyrosine also the of a signal transduction pathway in monocytic cells that involves the ligation of activation of the Syk tyrosine the of activation of the NF-κB transcription and the induction of for inflammatory mediator not to be in this cytochalasin D IL-1β message In types of monocytic cells that as THP-1, is a integrin-mediated signaling pathway that involves FAK and that to gene this a of is not that activation of the Syk tyrosine kinase is for integrin-mediated gene induction, as to the induction can the of tyrosine kinases be be to a causal role for Syk in integrin In addition, the events changes in tyrosine phosphorylation to of inflammatory gene message levels to be In monocytes, it is that integrin ligation induces activation of the IL-1β gene but not message A. J. and J. S. Cell. the cell integrin ligation leads to activation of increased transcription reporter and increases in IL-1β message However, it is not integrin-mediated changes in IL-1β message levels in cells are the or by other as changes in message or activation the role of NF-κB and of other transcription factors to be these observations important into integrin signal transduction in monocytic cells and a key role for tyrosine phosphorylation events. A. Baldwin and D. of of for reporter gene and and M. of for the also J. A. for with