The combined inactivation of tumor necrosis factor and interleukin-6 prevents induction of the major acute phase proteins by endotoxin

The constellation of changes known as the acute phase response (APR) is a cytokine-driven process initiated by tissue inflammation. The proinflammatory cytokines, TNF, IL-1 and IL-6, are considered to be the primary mediators of the APR. IL-6 and IL-1beta gene-deleted mice (Fattori et al., J. Exp. Med. 1994. 180: 1243-1250; Kopf et al., Nature 1994. 368: 339-342; Fantuzzi et al., J. Immunol. 1996. 157: 291-296, respectively), exhibit impaired APR to turpentine injection but only a slight reduction in plasma acute phase protein levels in response to lipopolysaccharide (LPS). This infers an important role for TNF in the LPS-induced APR, however, in the present study, normal APR to both turpentine and LPS were observed in TNF/LTalpha-deficient mice. A striking absence of elevated major acute phase proteins, SAP and SAA, was observed in mice deficient in TNF/LTalpha and IL-6, suggesting that TNF-alpha or LTalpha do indeed exert important nonredundant synergism in the IL-1/IL-6 primary response. The regulation of other parameters typically altered in an APR, body weight, blood glucose and haptoglobin, was normal in LPS-dosed TNF/LTalpha-deficient and wild-type mice. The observed transcriptional response for SAA and SAP in these TNF/LTalpha/IL-6-deficient mice, in lieu of elevated plasma levels, suggests that SAA and SAP expression is possibly posttranscriptionally regulated.