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Differential regulation of LPS-induced IL-1β and EL-1 receptor antagonist mRNA by IFN and IFN in murine peritoneal macrophages

Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, Bethesda, MD, USA

C.A. Salkowski

Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, Bethesda, MD, USA

A.D. Politis

Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, Bethesda, MD, USA

S.N. Vogel

Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, Bethesda, MD, USA

IL-1 and its naturally occurring receptor antagonist, IL-1ra, are primarily synthesized by cells of the monocyte-macrophage lineage. The balance of the relative amounts of these secreted cytokines has major importance in the pathophysiology of various inflammatory disorders, especially bacterial sepsis and some autoimmune diseases. While both the agonist and the antagonist genes belong to the same family, IL-1β and IL-1ra are differentially regulated. In the present study, we examined the effects of macrophage activating factors, bacterial lipopolysaccharide (LPS), IFN, and IFN, on the regulation of IL-1ra and IL-1β mRNA levels in thioglycollate-elicited mouse peritoneal macrophages. LPS-treatment of cultured macrophages resulted in a 3 to 4-fold increase in IL-1ra mRNA which peaked between 6-12 h, then started to decline but remained well above background levels at 24 h. In comparison to IL-1ra, the LPS-induced increase in IL-1β mRNA was larger, peaked earlier (at 2-4 h), and sharply decreased thereafter. In vivo analysis of mRNA from LPS-injected mice showed a similar temporal pattern of IL-1β and IL-1ra gene expression in bone marrow, spleen, and liver. In contrast to the effects of LPS, treatment with IFN and IFN alone failed to affect the expression of either IL-1ra or IL-1β mRNA in vitro. However, in combination with LPS, IFN and IFN had differential effects on the induction of these cytokines: IFN, but not IFN, augmented the expression of LPS-induced IL-1ra. Conversely, both IFN and IFN suppressed the induction of IL-1β mRNA by LPS. Thus, while IFN only affects LPS-induced IL-1β gene expression, IFN exerts opposing effects on the LPS-induction of the agonist and antagonist, illustrating the complex role of interferons during the inflammatory process.

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