Role of interferon-γ in counteracting the suppressive effects of transforming growth factor-β2 and glucocorticoids on the production of tumor necrosis factor-α

The multipotential cytokine, transforming growth factor-β2 (TGF-β2), is as effective as glucocorticoids in suppressing the production of tumor necrosis factor-α (TNF-α) by lipopolysaccharide (LPS)-stimulated macrophages, and this inhibition can be abrogated by exogenous interferon-γ (IFN-γ). Porcine alveolar macrophages triggered with LPS produce TNF-α as identified by complete blocking of cytotoxicity on WEHI 164 clone 13 cells in macrophage supernatants by a monoclonal antibody to human TNF-α. Platelet-derived porcine TGF-β2 at a concentration of 4 nM, inhibited LPS-induced production of TNF-α by 93%. Dexamethasone was as effective as TGF-β2, suppressing TNF-α production by 86% at a concentration of 4 nM. The natural but less potent glucocorticoid cortisol inhibited TNF-α production by 100% at a 100-fold higher concentration (400 nM). Recombinant PoIFN-γ consistently primed LPS-triggered macrophages for increased production of TNF-α by 50-100%, and this priming was totally blocked by a polyclonal antibody to rPoIFN-γ. Furthermore, the suppression in LPS-induced production of TNF-α caused by TGF-β2, dexamethasone, and cortisol could be reversed by addition of rPoIFN-γ. These data show that alveolar macrophages can be effectively primed by rPolIFN-γ even in the presence of moderately suppressive doses of TGF-β2 and antiiflammatory steriods.