Peroxisome proliferator-activated receptor-γ haploinsufficiency enhances B cell proliferative responses and exacerbates experimentally induced arthritis
Keigo Setoguchi, Yoshikata Misaki, Yasuo Terauchi, Toshimasa Yamauchi, Kimito Kawahata, Takashi Kadowaki, Kazuhiko Yamamoto
Keigo Setoguchi, Yoshikata Misaki, Yasuo Terauchi, Toshimasa Yamauchi, Kimito Kawahata, Takashi Kadowaki, Kazuhiko Yamamoto
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Peroxisome proliferator-activated receptor-γ haploinsufficiency enhances B cell proliferative responses and exacerbates experimentally induced arthritis

Abstract

Peroxisome proliferator–activated receptor-γ (PPARγ) controls adipogenesis and glucose metabolism. It was reported recently that PPARγ activation by its agonistic ligands modifies lymphocyte function. Since synthetic ligands are known to exert their effect via PPARγ-dependent and -independent pathways, we examined the physiological role of PPARγ in lymphocytes by using heterozygote mutant mice in which one allele of PPARγ is deleted (PPARγ+/–). In contrast to T cells, which did not exhibit a significant difference, B cells from PPARγ+/– showed an enhanced proliferative response to stimulation by either lipopolysaccharide or cross-linking of antigen receptors. Dysregulation of the NF-κB pathway in B cells from PPARγ+/– was indicated by spontaneous NF-κB activation, as well as increased IκBα phosphorylation and gel-shift activity following LPS stimulation. Mice primed with either ovalbumin or methylated BSA also showed enhanced antigen-specific immune response of both T and B cells, an immunological abnormality that exacerbated antigen-induced arthritis. These findings indicate that PPARγ plays a critical role in the control of B cell response and imply a role in diseases in which B cell hyperreactivity is involved, such as arthritis and autoimmunity.

Authors

Keigo Setoguchi, Yoshikata Misaki, Yasuo Terauchi, Toshimasa Yamauchi, Kimito Kawahata, Takashi Kadowaki, Kazuhiko Yamamoto

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Antigen-specific immune response was enhanced in PPARγ+/– mice. (a) Prol...
Antigen-specific immune response was enhanced in PPARγ+/– mice. (a) Proliferation of splenocytes from wild-type mice (open circles, +/+) and PPARγ+/– mice (filled circles, +/–), both of which were primed with OVA. Proliferation was measured by [3H]thymidine incorporation in the presence of various concentrations of OVA. Bars show the mean ± SD (n = 10 per group). The difference between the two groups was significant (*P < 0.01). (b) The level of Ab against OVA in sera from mice primed with OVA. Mice were bled 30 days after priming with OVA and assayed for the anti-OVA Ab level by ELISA. The mean Ab titers (± SD) of each group of ten mice are shown. The difference between the two groups was significant (*P < 0.01). (c) Proliferation against mBSA of splenocytes from mBSA-primed wild-type control mice (open circles, +/+) and PPARγ+/– mice (filled circles, +/–), respectively. Proliferation was measured by [3H]thymidine incorporation in the presence of various concentrations of mBSA. Bars show the mean ± SD (n = 10 per group).The difference between the two groups was significant (*P < 0.001). (d) Mice were bled 30 days after intra-articular challenge with mBSA and assayed for the anti-mBSA Ab level by ELISA. The mean Ab titers (± SD) of each group of the total ten mice are shown. The statistical difference between PPARγ+/– and PPARγ+/+ littermates derived from the same litter were significant (*P < 0.01).