Inhibition of lupus nephritis in IRF-1 deficient mice

Virginia Polytechnic Inst And St Univ, Blacksburg VA

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Abstract

DESCRIPTION (provided by applicant): MRL/Ipr mice spontaneously develop immune complex glomerulonephritis similar to human lupus. Prior to overt disease manifestations, MRL/lpr mice overproduce nitric oxide (NO) secondary to increased gene expression of inducible nitric oxide synthase (iNOS). Blockade of iNOS pharmacologically reduces disease expression in MRL/lpr mice. Both macrophages and mesangial cells respond to IFN-gamma with increased production of iNOS and this response can be potentiated further by the addition of TNF-a. IFN-gamma constitutes one of the most potent macrophage activating factors. Either IFN-7 or IFN-y receptor gene deletion modulates disease activity in lupus mice although other adverse effects in these genetic knockouts were noted. Mesangial cells are the principal immunoregulatory cells in the glomerulus possessing both macrophage and smooth muscle cell characteristics. In addition to expressing Fc receptors, mesangial cells contain receptors that bind cytokines and chemokines including receptors for IFN-gamma and TNF-oc. Binding of IFN-gamma to its receptor induces transcription of various genes including IFN-gamma regulatory factor 1 (IRF-1). Many of the inflammatory effects of IFN-gamma in macrophages and mesangial cells are mediated through IRF-1 including up-regulation of IL-12, vascular cell adhesion molecule 1, interferon-p, major histocompatability complex I, and iNOS. The molecular events triggered by IRF-1 activation leading to iNOS expression are not completely elucidated. We hypothesize that IRF-1 plays a key role in the initiation and propagation of the inflammatory response in the murine lupus kidney. Targeting IRF-1 may thus serve as a novel mechanism for blocking inflammation in the lupus kidney. The specific aims described below investigate the role of IFN-y signaling and define the role of IRF-1 in lupus nephritis in MRL/lpr mice. Specific Aim 1: Determine the relationship between IFN-gamma, IRF-1 and NFKB activation on inflammatory mediator production including iNOS, IL-12, COX2, and TNF-c in mesangial cells. We will also determine the effects of specific immune modulators on IFN-y signaling and IRF-1 expression in macrophages and mesangial cells from MRL/lpr IRF-1 (-/-, +/-, +/+), B6 IRF-1 (-/-) and control, wiId type mice stimulated with LPS/TNF-oc. Specific Aim 2: Study the in vivo effect of gene deletion of IRF-1 on MRL/lpr mice by backcrossing C57BL6 (IRF-1- /-) mice onto the MRL/lpr background.