Macrophages rapidly engulf apoptotic cells to limit the release of noxious cellular contents and to restrict autoimmune responses against self antigens. Although factors participating in recognition and engulfment of apoptotic cells have been identified, the transcriptional basis for the sensing and silently disposing of apoptotic cells is unknown. Here we show that peroxisome proliferator activated receptor-δ (PPAR-δ) is induced when macrophages engulf apoptotic cells and functions as a transcriptional sensor of dying cells. Genetic deletion of PPAR-δ decreases expression of opsonins, such as C1qb, resulting in impairment of apoptotic cell clearance and reduction in anti-inflammatory cytokine production. This increases autoantibody production and predisposes global and macrophage-specific PPARd−/− mice to autoimmune kidney disease, a phenotype resembling the human disease systemic lupus erythematosus. Thus, PPAR-δ plays a pivotal role in orchestrating the timely disposal of apoptotic cells by macrophages, ensuring that tolerance to self is maintained.

Abstract. The two major intermediate filament proteins in glandular epithelia are keratin polypeptides 8 and 18 (K8/18). To evaluate the function and potential disease association of K18, we examined the effects of mutating a highly conserved arginine (arg89) of K18. Expression of K18 arg89~his/cys and its normal K8 partner in cultured cells resulted in punctate staining as compared with the typical filaments obtained after expression of wild-type K8/18. Generation of transgenic mice expressing human K18 arg89~cys resulted in marked disruption of liver and pancreas keratin filament networks. The most prominent histologic abnormalities were liver inflammation and necrosis that appeared at a young age in association with hepatocyte fragility and serum transaminase elevation. These effects were caused by the mutation since transgenic mice expressing wild-type human K18 showed a normal phenotype. A relative increase in the phosphorylation and glycosylation of detergent solubilized K8/18 was also noted in vitro and in transgenic animals that express mutant K18. Our results indicate that the highly conserved arg plays an important role in glandular keratin organization and tissue fragility as already described for epidermal keratins. Phosphorylation and glycosylation alterations in the arg mutant keratins may account for some of the potential changes in the cellular function of these proteins. Mice expressing mutant K18 provide a novel animal model for human chronic hepatitis, and for studying the tissue specific function(s) of K8/18.

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The role of tumor necrosis factor a (TNF-a) in the pathogenesis of autoimmune diabetes mellitus was tested in the nonobese mouse (NOD) model system. The effects of TNF-a were assessed on three levels: (i) insulitis development, (ii) development of overt diabetes, (iii) adoptive transfer of diabetes by splenic lymphocytes. Spontaneous diabetes mellitus was blocked in NOD mice by long-term treatment with recombinant TNF-a. Treatment with TNF-a caused'a significant reduction in the lymphocytic infiltration associated with the destruction of the insulin-producing beta cells. Class II major histocompatibility complex Ia expression by islet cells was not up-regulated by TNF-a. Moreover, TNF-a was able to suppress the induction of diabetes in adoptive transfer of lymphocytes from diabetic female mice to young nondiabetic male NOD mice. These activities of TNF-a were shared by interleukin la in this system. These studies have implications for the pathogenesis and therapy of autoimmune diabetes mellitus.Nonobese diabetic (NOD) mice spontaneously develop diabetes remarkably similar to human autoimmune insulindependent diabetes mellitus. There is increasing evidence that the human and the NOD disease result from immune destruction of the insulin-producing beta cells in the islets of Langerhans (1). The disease is characterized by progressive lymphocyte infiltration into the islets (insulitis) prior to the expression of overt diabetes and by the appearance of anti-islet cell antibodies in the serum (2). A T-cell-mediated autoimmune pathogenesis is implicated because the disease can be passively transferred with lymphocytes into irradiated prediabetic mice (3) and prevented by treatment with antibodies directed against Thy-1.2 (4) and L3T4 (5) or by treatment with cyclosporin A (6). Diabetes can also be prevented by treatment with antibodies to class II Ia antigens (7). Untreated animals develop profound glucose intolerance and ketosis and die within weeks of the onset of overt diabetes. The role of lymphokines, especially interferon y (IFN-y), interleukin 1 (IL-1), and tumor necrosis factor a (TNF-a), in the pathogenesis of autoimmune diabetes has received increasing attention recently (8, 9). It was shown that IFN--y and TNF-a can induce the aberrant expression of class II major histocompatibility complex (MHC) molecules on pancreatic beta cells in vitro, suggesting a role for these lymphokines in the induction of the autoimmune process in diabetes (9). A different group of investigators has suggested that IL-1 is toxic to pancreatic beta cells in vitro and that TNF-a significantly enhances this toxicity (8). Recently we have suggested that TNF-a may play a significant role in preventing autoimmune nephritis in the (NZB3 x NZW)F1 lupus nephritis model system (10). Here we present evidence that TNF-a has a major effect in vivo by protecting NOD mice from developing autoimmune insulitis and diabetes. MATERIALS AND METHODSRecombinant murine TNF-a (0.53 mg/ml; 2.6 x 107 units/ml) was kindly provided by Genentech. Recom...

In adult mice, the dominant adhesion molecules involved in homing to lymph nodes are L-selectin homing receptors on lymphocytes and the peripheral lymph node addressins on specialized high endothelial venules. Here we show that, from fetal life through the rst 24 hr of life, the dominant adhesion molecules are the mucosal addressin MAdCAM-1 on lymph node high endothelial venules and its counterreceptor, the Peyer's patch homing receptor, integrin a4(87 on circulating cells. Before birth, 40-70%o of peripheral blood leukocytes are L-selectin-positive, while only 1-2% expresses a4,B7. However, the fetal lymph nodes preferentially attract a487-expressing cells, and this can be blocked by fetal administration of anti- 4).The primary adhesion molecules are involved in initial "rolling" contacts, to be followed by secondary adhesive events required for arrest and subsequent transendothelial migration of these cells (5-7). To enter an adult peripheral LN (PLN), lymphocytes express high levels of the homing receptor Lselectin (8)(9)(10)(11) 11019The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.