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 ag ainst intracellular pathogens. Various mechanisms are employed to control t he activation processes and limit tissue damage by factors produced by acti vated macrophages. One of these mechanisms is the production of macrophage- deactivating cytokines, such as tumour growth factor (TGF)-beta. The presen t study concerns the effects of TGF-beta on interferon (IFN)-gamma -induced activation of murine macrophages with respect to induction of toxoplasmast atic activity, and production of tumour necrosis factor (TNF)-alpha, prosta glandin E-2 (PGE(2)) and reactive nitrogen intermediates (RNI). IFN-gamma a ctivation of macrophages resulted in inhibition of T. gondii proliferation [mean fold increase (FI)= 1.8, control mean FI = 7.0]; polymyxin B had no e ffect on this activation. The IFN-gamma -induced toxoplasmastatic activity of macrophages was inhibited by TGF-beta (mean Fl = 6.3), which was also fo und for the IFN-gamma -induced production of TNF-alpha, RNI and PGE(2) by m acrophages. We found that PGE(2), which has macrophage deactivating propert ies, was not involved in the inhibition of macrophage activation by TGF-bet a. The deactivating activities of TGF-beta on the IFN-gamma -induced toxopl asmastatic activity and production of RNI are mediated by inhibition of pro duction of TNF-alpha. Addition of exogenous TNF-alpha during the incubation of macrophages with IFN-gamma and TGF-beta abrogated the deactivating acti vity of TGF-beta. In sum, the results demonstrate that inhibition of TNF-al pha production is a key factor in the TGF-beta -induced suppression of macr ophage activation with respect to toxoplasmastatic activity and RNI product ion.