The role of tumour necrosis factor-α in combination with interferon-γ or interleukin-1 in the induction of immunosuppressive macrophages because of Mycobacterium avium complex infection

Abstract

The role of some cytokines including tumour necrosis factor-α (TNF-α), interleukin-1α (IL-1α), interferon-γ (IFN-γ), transforming growth factor-β (TGF-β) and interleukin-6 (IL-6) in the generation of immunosuppressive macrophages (MΦs) in host spleen cells of Mycobacterium avium complex (MAC)-infected mice was studied. MΦ populations with potent suppressor activity against concanavalin A (Con A)-induced mitogenesis of splenocytes (SPCs) were elicited not only in euthymic but also in athymic nude mice during MAC infection. The suppressor MΦs are, therefore, inducible not only through a T-cell-dependent mechanism but also through T-cell-independent mechanism. However, MAC-induced MΦs of athymic mice displayed about four times lower suppressor activity than those of euthymic mice, indicating that mature T cells are important for MΦ activation to the highly immunosuppressive state. Anti-TNF, anti-IFN-γ, and anti-TGF-β antibodies (Abs) but not anti-IL-6 Ab inhibited in vivo generation of MAC-induced immunosuppressive MΦs, and the neutralizing efficacy was in the order of anti-IFN-γ Ab > anti-TNF Ab > anti-TGF-β Ab. The effects of TNF-α, IL-1α, IL-6, and IFN-γ alone or combinations of them upon the acquisition of the suppressor activity by cultured splenic MΦs were studied. When normal splenic MΦs were treated with each cytokine for 3 days, TNF-α, IFN-γ, and IL-1α alone caused a slight elevation of their suppressive activity. Treatment of the normal MΦs with the combination of either TNF-α + IL-1α or TNF-α + IFN-γ yielded a marked increase in the suppressor activity, followed by IL-1α + IFN-γ. These findings indicate the important roles of TNF-α, IFN-γ, and IL-1α in the generation of MAC-induced suppressor MΦs.