Role of interferon-gamma in counteracting the suppressive effects of transforming growth factor-beta 2 and glucocorticoids on the production of tumor necrosis factor-alpha.
The multipotential cytokine, transforming growth factor-beta 2 (TGF-beta 2), is as effective as glucocorticoids in suppressing the production of tumor necrosis factor-alpha (TNF-alpha) by lipopolysaccharide (LPS)-stimulated macrophages, and this inhibition can be abrogated by exogenous interferon-gamma (IFN-gamma). Porcine alveolar macrophages triggered with LPS produce TNF-alpha as identified by complete blocking of cytotoxicity on WEHI 164 clone 13 cells in macrophage supernatants by a monoclonal antibody to human TNF-alpha. Platelet-derived porcine TGF-beta 2, at a concentration of 4 nM, inhibited LPS-induced production of TNF-alpha by 93%. Dexamethasone was as effective as TGF-beta 2, suppressing TNF-alpha production by 86% at a concentration of 4 nM. The natural but less potent glucocorticoid cortisol inhibited TNF-alpha production by 100% at a 100-fold higher concentration (400 nM). Recombinant PoIFN-gamma consistently primed LPS-triggered macrophages for increased production of TNF-alpha by 50-100%, and this priming was totally blocked by a polyclonal antibody to rPoIFN-gamma. Furthermore, the suppression in LPS-induced production of TNF-alpha caused by TGF-beta 2, dexamethasone, and cortisol could be reversed by addition of rPoIFN-gamma. These data show that alveolar macrophages can be effectively primed by rPoIFN-gamma even in the presence of moderately suppressive doses of TGF-beta 2 and antiinflammatory steroids.
Dunham
D M
DM
Department of Animal Sciences, University of Illinois, Urbana 61801.
Arkins
S
S
Edwards
C K
CK
Dantzer
R
R
Kelley
K W
KW
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D002460:Cell Line; D003907:Dexamethasone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005938:Glucocorticoids / Q000494:pharmacology*; D006854:Hydrocortisone / Q000494:pharmacology; D007371:Interferon-gamma / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology; D051379:Mice; D011650:Pulmonary Alveoli / Q000276:immunology; D011994:Recombinant Proteins; D013552:Swine; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
D000911:Antibodies, Monoclonal; D005938:Glucocorticoids; D008070:Lipopolysaccharides; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D003907:Dexamethasone; D007371:Interferon-gamma; D006854:Hydrocortisone