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Distinct Pathways for NF-B Regulation Are Associated with Aberrant Macrophage IL-12 Production in Lupus- and Diabetes-Prone Mouse Strains¹

Arthritis Section, Evans Department of Medicine and Clinical Research, Boston University Medical Campus, Boston, MA 02118

One characteristic of mice prone to a variety of autoimmune diseases is the aberrant regulation of cytokine production by macrophages (M), noted in cells isolated well before the onset of disease. Strikingly, the pattern of IL-12 dysregulation, in particular, is consistent with the nature of the autoimmune disease that will develop in each strain, i.e., elevated in mice prone to Th1-mediated organ-specific disease (nonobese diabetic (NOD) and SJL mice) and reduced in lupus-prone strains (MRL/+ and NZB/W). Mechanistically, the abnormal regulation of IL-12 in these strains was found to be strictly associated with novel patterns of Rel binding in vitro to the unique NF-B site in the IL-12 p40 promoter. In this study, we report several new findings related to these Rel-B interactions. Evaluation of the p40 NF-B site in vivo, assessed by chromatin immunoprecipitation, revealed Rel usage patterns similar to those found in vitro using EMSA, with preferential association of the p40 B site with c-Rel in NOD M but with p50 in NZB/W M. Moreover, blocking c-Rel in primary M, using short interfering RNA, selectively blocked IL-12 production and normalized the minimal, residual IL-12 levels. Nuclear extracts from NOD M were characterized by c-Rel hyperphosphorylation, and dephosphorylation of nuclear proteins completely blocked binding to the B site. In contrast, elevated IB appears to be a likely mechanism accounting for the reduced nuclear c-Rel levels noted in NZB/W M. Alterations in NF-B metabolism thus appear to define a pathway regulating intrinsic IL-12 defects in both diabetes- and lupus-prone strains.

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