| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2005: ¥1,100,000 (Direct Cost: ¥1,100,000)
Fiscal Year 2004: ¥1,100,000 (Direct Cost: ¥1,100,000)
Fiscal Year 2003: ¥1,300,000 (Direct Cost: ¥1,300,000)
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| Research Abstract |
Integrins are major adhesion receptors that regulate cytoskeletal organization and cell motility. They also trigger a variety of signal transduction pathways and specific gene expression. The present study was designed to determine the modulatory effects of accumulation of extracellular matrix (ECM) proteins observed in various types of human and experimental glomerulonephritis on the expression of inflammatory-related genes involved in the progression of renal diseases. We examined the effects of integrin-mediated signaling on the expression of intracellular adhesion molecule (ICAM)-1 and co-stimulatory factors, CD80 and CD86 in cultured human mesangial cells by FACS analysis. Quiescent mesangial cells (MC) abundantly expressed cell surface molecules such as alpha 2,3,4,5 and beta 1 integrins, CD44,CD80, and CD95 and weakly alpha 6 and v and beta 3 integrins, ICAM-1, and Fas, while MC did not express CD40,CD154 (40L),CD86, and VCAM-1. Stimulation of beta 1 integrin by ligation using a
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specific monoclonal antibody against beta 1 integrin, mAb13, induced time-dependent transient expression of only ICAM-1 and CD80. Stimulation of MHC class I, ICAM-1, and VCAM-1 did not alter expression level of ICAM-1. Cell adhesion to ECM proteins, e.g., type I and III collagens, which have affinity for alpha 2 beta 1 integrin, effectively enhanced ICAM-1 expression, however, adhesion to other ECM proteins, non-specific adhesion substrates and serum albumin had no effect on ICAM-1 expression. Furthermore, pretreatment of cells with anti-alpha 2 integrin inhibitory antibody completely inhibited beta 1 integrin-induced expression of ICAM-1, although antibodies against alpha 1,5, and v integrins failed to block ICAM-1 expression. Similarly, type I and III collagens-induced expression of ICAM-1 was suppressed by pretreatment of cells with anti-alpha 2 antibody. Treatment of cells with a MAP kinase kinase (MEK) inhibitor, PD98059, tyrosin kinase inhibitor, genistein, or protein kinase C (PKC) inhibitor, calphostin C, suppressed levels of beta 1 integrin-induced ICAM-1 expression. Increased expression of ICAM-1 was accompanied by altered cell adhesion between mesangial cells and leukocytes. These results indicate that stimulation of alpha 2 beta 1 integrin induces ICAM-1 expression through tyrosin kinases and PKC, and suggest that accumulation of pathological ECM components such as type I and III collagens might play a role in the progression of glomerular diseases by enhancing ICAM-1 expression. Less
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