Cyclosporine A regulates T cell-epithelial cell adhesion by altering LFA-1 and ICAM-1 expression.
In contrast to the well characterized suppressive effect of cyclosporine A (CsA) on IL-2 gene transcription in T cells, other immunosuppressive effects of CsA have received less attention. We have examined the effect of CsA on the expression of the beta 2 integrin, LFA-1, and its counter receptor, ICAM-1, on a renal Ag-specific murine T cell clone and Ag-expressing renal tubular epithelial cells. We have found that CsA has a concentration dependent effect on the expression of both ICAM-1 mRNA and gene product on renal tubular cells. At 0.1 microgram/ml, CsA exhibits a costimulatory effect, with TNF alpha, on ICAM-1 expression. CsA at 1 to 5 micrograms/ml exhibits concentration dependent inhibition of ICAM-1 cell surface expression by the tubular cells. Although CsA does not inhibit ICAM-1 on T cells, it does inhibit surface expression of LFA-1. The concentration dependent effects of CsA on ICAM-1 expression correlate well with ICAM-1 dependent T cell adhesion to TNF alpha stimulated tubular epithelial cells. TGF-beta 1 has similar effects on ICAM-1 and LFA-1 expression as high dose CsA, but the CsA effects are not mediated through induced TGF-beta 1 expression. Our studies support the conclusion that CsA may bidirectionally alter ICAM-1 dependent cellular adhesive interactions. The inhibition of cytokine stimulated ICAM-1 expression at higher CsA concentrations would contribute to the overall immunosuppressive effect of the drug.
Frishberg
Y
Y
Division of Nephrology-Hypertension, University of California, San Diego, USA.
Meyers
C M
CM
Kelly
C J
CJ
D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects; D002460:Cell Line; D016572:Cyclosporine / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects*; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics*; D007684:Kidney Tubules / Q000187:drug effects / Q000378:metabolism; D016169:Lymphocyte Function-Associated Antigen-1 / Q000235:genetics*; D051379:Mice; D012333:RNA, Messenger / Q000032:analysis; D013601:T-Lymphocytes / Q000187:drug effects* / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D007166:Immunosuppressive Agents; D016169:Lymphocyte Function-Associated Antigen-1; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; D016572:Cyclosporine