Tumor-induced modulation of macrophage class II MHC molecule mRNA expression

Abstract

Class II MHC protein expression in macrophages (Mϕ) 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 Mϕ responsiveness to an inducing agent, such as interferon-γ (IFN-γ), or (ii) an increase in Mϕ sensitivity to suppressing agents, such as prostaglandin E 2 (PGE 2). To determine how tumors induce suppression of class II mRNA, Mϕ were cultured in the presence of IFN-γ with or without other factors, and Northern blot analyses were performed. Unstimulated normal host (NH) or tumor-bearing host (TBH) Mϕ do not express detectable class II mRNA. The addition of IFN-γ induces class II mRNA expression in NH and TBH Mϕ, but class II mRNA expression is significantly lower in TBH Mϕ. Kinetic studies suggested that NH Mϕ class II mRNA is induced faster and in greater amounts than TBH Mϕ class II mRNA. There is a decrease in Mϕ class II mRNA stability during tumor growth that may account for the decreased induction by IFN-γ. Lipopolysaccharide (LPS) suppresses class II mRNA induction in both NH and TBH IFN-γ-treated Mϕ but TBH Mϕ are more sensitive to its suppression. PGE 2 and tumor-necrosis factor-α (TNF-α), two factors produced by LPS-stimulated Mϕ, were tested for their ability to modulate class II mRNA expression in NH and TBH IFN-γ-treated Mϕ. PGE 2 suppressed class II mRNA expression in both NH and TBH Mϕ. The addition of TNF-α to IFN-γ-treated Mϕ suppressed class II mRNA in NH Mϕ but, surprisingly, had an additive effect on IFN-γ-induced class II mRNA expression. TNF-α did not induce class II mRNA expression in TBH Mϕ in the absence of IFN-γ. The cause of the reduced class II mRNA expression during tumor growth is a decreased response to IFN-γ and an increased sensitivity to PGE 2. This change may cause the observed suppression mediated by TBH Mϕ.