Functional switching of macrophage responses to tumor necrosis factor-α (TNFα) by interferons : implications for the pleiotropic activities of TNFα

• Published in: The Journal of clinical investigation 1994-04, Vol.93 (4), p.1661-1669
• Main Authors: LAKE, F. R, NOBLE, P. W, HANSON, P. M, RICHES, D. W. H
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Complement Factor B - biosynthesis; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Hyaluronic Acid - pharmacology; Immunobiology; Insulin-Like Growth Factor I - biosynthesis; Insulin-Like Growth Factor I - genetics; Interferons - pharmacology; Interferons - physiology; Macrophages - drug effects; Macrophages - physiology; Mice; Mice, Inbred C3H; Monocytes, macrophages; Myeloid cells: ontogeny, maturation, markers, receptors; Poly I-C - pharmacology; Receptors, Tumor Necrosis Factor - physiology; Recombinant Proteins - pharmacology; RNA, Messenger - analysis; Tumor Necrosis Factor-alpha - genetics; Tumor Necrosis Factor-alpha - pharmacology; Tumor Necrosis Factor-alpha - physiology
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/jci117148

Recent work conducted in our laboratory has been directed towards understanding the role of TNF alpha in stimulating the synthesis of two macrophage gene products, namely IGF-1, a growth factor implicated in wound repair and fibrosis, and complement component factor B (Bf), an alternative pathway complement component. The expression of these proteins is induced by hyaluronic acid and poly (I:C), respectively, although TNF alpha plays a requisite role in the expression of both proteins. The objective of this study was to determine the mechanism governing the dichotomy in the expression of IGF-1 and Bf by TNF alpha. First, we questioned if the diversity in IGF-1 and Bf synthesis was regulated at the level of TNF receptor usage. Second, based on earlier findings that IFNs contribute to the initiation of Bf expression, we determined if IFNs modulate the response of macrophages to TNF alpha. Our data show that differences in TNF receptor usage cannot fully explain the dichotomy in the expression of IGF-1 and Bf. However, prior exposure to IFN-beta or IFN-gamma was found to be a dominant factor controlling the expression of these proteins, suppressing IGF-1, and enhancing Bf. These findings indicate that IFNs mediate a functional "switch" in the response of macrophages to TNF alpha and suggest that the pattern of cytokine expression by diverse macrophage stimuli is an important determinant of the eventual responses of macrophages to TNF alpha.