Retinoic acids, a group of natural and synthetic vitamin A derivatives, have potent antiproliferative and anti-inflammatory properties. Recently, retinoic acids were reported to inhibit Th1 cytokine production. We investigated the effects of retinoic acid on lupus nephritis in a model of NZB/NZW F1 (NZB/W F1) mice. Three-month-old NZB/W F1 mice were separated into two groups: one treated with all-trans-retinoic acid (ATRA; 0.5 mg i.p., three times weekly for 7 mo) and one with saline as a control. Compared with controls, ATRA-treated mice survived longer and exhibited a significant reduction of proteinuria, renal pathological findings including glomerular IgG deposits, and serum anti-DNA Abs. Splenomegaly was less marked in the treated mice than in controls. Transcripts encoding IFN-γ, IL-2, and IL-10 in splenic CD4+ T cells were significantly reduced in treated mice compared with controls. We conclude that treatment with ATRA in SLE-prone NZB/W F1 mice significantly alleviates autoimmune renal disorder and prolongs survival; this may thus represent a novel approach to the treatment of patients with lupus nephritis.

Background: Cardiolipin is required for maintaining optimal mitochondrial function. Results: Cardiolipin depletion selectively obstructed proliferation, mitochondrial function, and morphology in germ cells. Conclusion: The contribution of cardiolipin to mitochondrial function and morphology varies among the different cell types in vivo.Significance: This provides a biological basis for understanding the different sensitivities of organelles to changes in the lipid environment.Cardiolipin (CL) is a major membrane phospholipid specifically localized in mitochondria. At the cellular level, CL has been shown to have a role in mitochondrial energy production, mitochondrial membrane dynamics, and the triggering of apoptosis. However, the in vivo role of CL in multicellular organisms is largely unknown. In this study, by analyzing deletion mutants of a CL synthase gene (crls-1) in Caenorhabditis elegans, we demonstrated that CL depletion selectively caused abnormal mitochondrial function and morphology in germ cells but not in somatic cell types such as muscle cells. crls-1 mutants reached adulthood but were sterile with reduced germ cell proliferation and impaired oogenesis. In the gonad of crls-1 mutants, mitochondrial membrane potential was significantly decreased, and the structure of the mitochondrial cristae was disrupted. Contrary to the abnormalities in the gonad, somatic tissues in crls-1 mutants appeared normal with respect to cell proliferation, mitochondrial function, and mitochondrial morphology. Increased susceptibility to CL depletion in germ cells was also observed in mutants of phosphatidylglycerophosphate synthase, an enzyme responsible for producing phosphatidylglycerol, a precursor phospholipid of CL. We propose that the contribution of CL to mitochondrial function and morphology is different among the cell types in C. elegans. Cardiolipin (CL)2 is an anionic phospholipid with a unique diphosphatidylglycerol structure containing four acyl groups (1-3). In eukaryotic cells, CL localizes predominantly to the mitochondrial inner membrane, where it serves specific roles in mitochondrial structure and function. CL biosynthesis occurs via three enzymatic reactions, all catalyzed by enzymes present in the mitochondria (Fig. 1A) (4). The first step, catalyzed by phosphatidylglycerophosphate (PGP) synthase, is the synthesis of PGP from cytidine diphosphate-diacylglycerol (CDP-DAG) and glycerol 3-phosphate. PGP phosphatase dephosphorylates PGP to phosphatidylglycerol (PG). In the final step, CL synthase catalyzes the formation of CL from PG and CDP-DAG. These enzymes are highly conserved in eukaryotes (Figs. 1A, 2B, and 9B) (5).So far, in vitro analysis has revealed that CL interacts with a number of mitochondrial proteins and is required for the optimal activity of several enzymes in the mitochondrial electron transport chain, including NADH dehydrogenase (complex I) (6), ubiquinol:cytochrome c reductase (complex III) (7-10), cytochrome c oxidase (complex IV) (11,12), and ATP synthase (complex V) (13). Consi...

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It has been reported that apoptotic cells are increased in the peripheral blood from patients with systemic lupus erythematosus (SLE), where dysfunctions of T helper 1 (Th1) cells are known. In order to study whether apoptosis of Th1 cells is associated with the pathogenesis of SLE, early apoptotic cells in various T-cell subsets were detected using fluorescence-labeled annexin V (AnV). AnV binding was most frequently observed in CD4+CCR5+ T cells, and AnV binding rate (%) in this subset was higher in SLE than in normal controls (14.7 +/- 2.6), although that in active SLE (43.6 +/- 7.3) tended to be lower than that in inactive SLE (48.0 +/- 6.8). CD95/Fas expression was also increased in both active and inactive SLE. In some SLE patients, AnV binding rate changed in inverse proportion to titer of the serum anti-DNA antibody and in proportion to serum complement activity. These data suggest that apoptosis in Th1 cells is important in the pathogenesis of SLE and might play a role in regulating over-activation or autoreactive responses by T cells.