Interleukin-1 and tumor necrosis factor receptor modulation of the acute phase response to inflammation.

Abstract

The acute phase response (APR) to inflammation is mediated in part by the interaction of the endogenous cytokines interleukin-1 (IL-1) and tumor necrosis factor-$\alpha$ (TNF-$\alpha$) with their membrane-associated receptors. The hypothesis that endogenous IL-1 type I receptors (IL-1RtI) are involved in the APR to inflammation was tested in a rat model using the IL-1RtI antagonist (IL-1ra) and an IL-1RtI knockout mouse model. The role of the endogenous TNF receptors in the APR to inflammation was tested in knockout mice lacking TNF type I and type II receptors. The injection of IL-1ra into the lateral ventricle of rats resulted in a blockade of central IL-1$\beta$ fever and a partial attenuation of fever to a systemic inflammation induced by peripherally injected lipopolysaccharide (LPS). In contrast, knockout mice lacking the IL-1RtI developed an APR to the ip injection of a low and high dose of LPS that did not differ from wildtype mice possessing the IL-1RtI. These knockout mice were resistant to the fever, lethargy, anorexia and loss of body weight to a local inflammation induced by the subcutaneous (sc) injection of turpentine and were unresponsive to exogenous murine IL-1$\beta$. These results suggest that (1) the lack of IL-1Rtl signaling can be compensated for by the exacerbated release or activity of other APR-modulating cytokines such that the host defense is not completely compromised in response to systemic inflammation, and (2) the IL-1Rtl is a key mediator in the APR elicited to a sc injection of turpentine. Knockout mice lacking both the TNF type I and II receptors developed an exacerbated early phase of fever to the ip injection of a high dose of LPS suggesting an endogenous cryogenic or antipyretic role of endogenous TNF in this response. These mice were similar with respect to all acute phase responses monitored to a low dose of LPS and a sc injection of turpentine. These results suggest that TNF receptors (1) modulate fevers to LPS dose-dependently and, either (2) do not mediate the APR elicited to a low dose of LPS or the local inflammatory agent turpentine, or (3) have been compensated for by alternative mechanisms in the knockout mice which may have taken over their role in the mediation of the APR to a low dose of LPS or turpentine.