TUMOR-INDUCED MODULATION OF MACROPHAGE CLASS-II MHC MOLECULE MESSENGER-RNA EXPRESSION

Class II MHC protein expression in macrophages (Mphi) is reduced during tumor growth. Because regulation of class II MHC proteins occurs during transcription, tumor growth may suppress class II MHC protein expression by suppressing mRNA. The decrease in class II mRNA may result from (i) a decrease in Mphi responsiveness to an inducing agent, such as interferon-gamma (IFN-gamma), or (ii) an increase in Mphi sensitivity to suppressing agents, such as prostaglandin E2 (PGE2). To determine how tumors induce suppression of class II mRNA, Mphi were cultured in the presence of IFN-gamma with or without other factors, and Northern blot analyses were performed. Unstimulated normal host (NH) or tumor-bearing host (TBH) Mphi do not express detectable class II mRNA. The addition of IFN-gamma induces class II mRNA expression in NH and TBH Mphi, but class II mRNA expression is significantly lower in TBH Mphi. Kinetic studies suggested that NH Mphi class II mRNA is induced faster and in greater amounts than TBH Mphi class II mRNA. There is a decrease in Mphi class II mRNA stability during tumor growth that may account for the decreased induction by IFN-gamma. Lipopolysaccharide (LPS) suppresses class II mRNA induction in both NH and TBH IFN-gamma-treated Mphi, but TBH Mphi are more sensitive to its suppression. PGE2 and tumor-necrosis factor-alpha (TNF-alpha), two factors produced by LPS-stimulated Mphi, were tested for their ability to modulate class II mRNA expression in NH and TBH IFN-gamma-treated Mphi. PGE2 suppressed class II mRNA expression in both NH and TBH Mphi. The addition of TNF-alpha to IFN-gamma-treated Mphi suppressed class II mRNA in NH Mphi but, surprisingly, had an additive effect on IFN-gamma-induced class II mRNA expression. TNF-alpha did not induce class II mRNA expression in TBH Mphi in the absence of IFN-gamma. The cause of the reduced class II mRNA expression during tumor growth is a decreased response to IFN-gamma and an increased sensitivity to PGE2. This change may cause the observed suppression mediated by TBH Mphi.