FUNCTIONAL SWITCHING OF MACROPHAGE RESPONSES TO TUMOR-NECROSIS-FACTOR-ALPHA (TNF-ALPHA) BY INTERFERONS - IMPLICATIONS FOR THE PLEIOTROPIC ACTIVITIES OF TNF-ALPHA

Recent work conducted in our laboratory has been directed towards unde rstanding the role of TNF alpha: in stimulating the synthesis of two m acrophage gene products, namely IGF-1, a growth factor implicated in w ound repair and fibrosis, and complement component factor B (Bf), an a lternative pathway complement component. The expression of these prote ins is induced by hyaluronic acid and poly(I:C), respectively, althoug h 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, w e 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 s how that differences in TNF receptor usage cannot fully explain the di chotomy 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 th e expression of these proteins, suppressing IGF-1, and enhancing Bf. T hese findings indicate that IFNs mediate a functional ''switch'' in th e response of macrophages to TNF alpha and suggest that the pattern of cytokine expression by diverse macrophage stimuli is an important det erminant of the eventual responses of macrophages to TNF alpha.