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

Class II MHC protein expression in macrophages (Mphi) is reduced durin g tumor growth. Because regulation of class II MHC proteins occurs dur ing transcription, tumor growth may suppress class II MHC protein expr ession by suppressing mRNA. The decrease in class II mRNA may result f rom (i) a decrease in Mphi responsiveness to an inducing agent, such a s interferon-gamma (IFN-gamma), or (ii) an increase in Mphi sensitivit y 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 a ddition of IFN-gamma induces class II mRNA expression in NH and TBH Mp hi, but class II mRNA expression is significantly lower in TBH Mphi. K inetic studies suggested that NH Mphi class II mRNA is induced faster and in greater amounts than TBH Mphi class II mRNA. There is a decreas e in Mphi class II mRNA stability during tumor growth that may account for the decreased induction by IFN-gamma. Lipopolysaccharide (LPS) su ppresses class II mRNA induction in both NH and TBH IFN-gamma-treated Mphi, but TBH Mphi are more sensitive to its suppression. PGE2 and tum or-necrosis factor-alpha (TNF-alpha), two factors produced by LPS-stim ulated Mphi, were tested for their ability to modulate class II mRNA e xpression 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, sur prisingly, had an additive effect on IFN-gamma-induced class II mRNA e xpression. TNF-alpha did not induce class II mRNA expression in TBH Mp hi 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 a nd an increased sensitivity to PGE2. This change may cause the observe d suppression mediated by TBH Mphi.