LIPOPOLYSACCHARIDE (LPS) DOWN-REGULATES CD4 EXPRESSION IN PRIMARY HUMAN MACROPHAGES THROUGH INDUCTION OF ENDOGENOUS TUMOR-NECROSIS-FACTOR (TNF) AND IL-1-BETA

The regulation of CD4 expression on macrophages and its role in immune cell interactions remain obscure. In contrast with primary lymphocyte s, primary macrophages express only low amounts of surface CD4, which is regulated differentially for example by adherence in vitro. We repo rt that addition of LPS for 1-5 days to human blood monocyte tissue cu lture-derived macrophages (TCDM) down-regulates both surface CD4 expre ssion and total cellular CD4 antigen content as measured by flow cytom etry and Western blot analysis. TNF-alpha and IL-1 beta, proinflammato ry cytokines which are both induced by LPS, also down-regulate surface and total CD4 expression in TCDM. This down-regulation of CD4 express ion by LPS, TNF-alpha, and IL-1 beta occurs at the level of transcript ion. The decreased macrophage CD4 expression induced by LPS was blocke d by MoAbs directed against human TNF-alpha and IL-1 beta, demonstrati ng that LPS acts on CD4 expression through induction of endogenous TNF -alpha and IL-1 beta. Conversely, neither LPS nor TNF-alpha and IL-1 b eta were able to modulate surface CD4 expression on quiescent or phyto haemagglutinin (PHA)-activated lymphocytes. Of other cytokines and gro wth factors tested, Th2 cytokines (IL-4, IL-10, IL-13), chemokines (MC P-1, MIP-1 alpha, RANTES), and macrophage colony-stimulating factor di d not alter CD4 expression in primary macrophages; granulocyte-monocyt e colony-stimulating factor and the prototypal Th1 cytokine interferon -gamma (IFN-gamma) modulated surface CD4 expression only after prolong ed treatment (5 days). Our results show that LPS, TNF-alpha and IL-1 b eta selectively down-regulate CD4 expression in primary human macropha ges, and that decreased CD4 expression induced by LPS results from end ogenous secretion of TNF-alpha and IL-1 beta by the macrophages.