Transforming growth factor-beta suppresses interferon-gamma-induced toxoplasmastatic activity in murine macrophages by inhibition of tumour necrosis factor-alpha production

Activation of macrophages plays an important role in the host resistance against intracellular pathogens. Various mechanisms are employed to control the activation processes and limit tissue damage by factors produced by activated macrophages. One of these mechanisms is the production of macrophage-deactivating cytokines, such as tumour growth factor (TGF)-beta. The present study concerns the effects of TGF-beta on interferon (IFN)-gamma-induced activation of murine macrophages with respect to induction of toxoplasmastatic activity, and production of tumour necrosis factor (TNF)-alpha, prostaglandin E2 (PGE2) and reactive nitrogen intermediates (RNI). IFN-gamma activation of macrophages resulted in inhibition of T. gondii proliferation mean fold increase (FI) = 1.8, control mean FI = 7.0]; polymyxin B had no effect on this activation. The IFN-gamma-induced toxoplasmastatic activity of macrophages was inhibited by TGF-beta (mean FI = 6.3), which was also found for the IFN-gamma-induced production of TNF-alpha, RNI and PGE2 by macrophages. We found that PGE2, which has macrophage deactivating properties, was not involved in the inhibition of macrophage activation by TGF-beta. The deactivating activities of TGF-beta on the IFN-gamma-induced toxoplasmastatic activity and production of RNI are mediated by inhibition of production of TNF-alpha. Addition of exogenous TNF-alpha during the incubation of macrophages with IFN-gamma and TGF-beta abrogated the deactivating activity of TGF-beta. In sum, the results demonstrate that inhibition of TNF-alpha production is a key factor in the TGF-beta-induced suppression of macrophage activation with respect to toxoplasmastatic activity and RNI production.