REGULATION OF RANTES AND ICAM-1 EXPRESSION IN MURINE MESANGIAL CELLS

Chemokines and adhesion molecules play a pivotal role in leukocyte inf iltration during tissue injury. RANTES (regulated upon activation, nor mal T cell expressed and secreted) is a monocyte chemoattractant that induces the expression of CD11/CD18 integrins on leukocytes for which intercellular adhesion molecule-1 (ICAM-1) is the ligand. Both RANTES and ICAM-1 can be expressed by mesangial cells (MC) in culture and in glomeruli during immune injury. In this study, the role of reactive ox ygen species (ROS) in the activation of RANTES and ICAM-1 in murine MC was examined. Tumor necrosis factor alpha (TNF-alpha) and aggregated immunoglobulin (aggr. Ig) G, which enhance ROS formation in MC, increa sed mRNA transcripts of both RANTES and ICAM-1. Thiol-containing free- radical scavengers N-acetyl cysteine, dimethyl- and tetramethylthioure a, or pyrrolidinedithiocarbamate abrogated the increase in mRNA for RA NTES and ICAM-1 in response to TNF-alpha or IgG. Hydroxy-methoxy aceto phenone, an inhibitor of NADPH-dependent oxidase, also attenuated RANT ES and ICAM-1 in response to TNF-alpha or IgG. ROS generated by additi on of xanthine oxidase and hypoxanthine induced RANTES and ICAM-1 expr ession, whereas hydrogen peroxide caused no response. Because cAMP can interfere with gene activation in MC, the effects of 8-Br-cAMP, forsk olin, and prostaglandin E(2) on mRNA levels were examined for RANTES a nd ICAM-1. These agents attenuated the response to IgG aggregates and also to superoxide generation. Finally, the effect of glucocorticoids, which are frequently used in glomerular immune injury, was examined. Dexamethasone decreased mRNA for both RANTES and ICAM-1 after stimulat ion with aggr. IgG or TNF-alpha. Both forskolin and dexamethasone also reduced the amount of RANTES protein secreted by MC in response to ag gr. IgG. Only dexamethasone decreased RANTES secretion in response to TNF-alpha stimulation. The inhibitory effects of cAMP and dexamethason e may explain the beneficial effects of cAMP mimetics, such as prostag landin E, and glucocorticoid administration on glomerular inflammatory processes.