Peroxisome proliferator-activated receptor-γ haploinsufficiency enhances B cell proliferative responses and exacerbates experimentally induced arthritis
Keigo Setoguchi, … , Takashi Kadowaki, Kazuhiko Yamamoto
Keigo Setoguchi, … , Takashi Kadowaki, Kazuhiko Yamamoto
Published December 1, 2001
Citation Information: J Clin Invest. 2001;108(11):1667-1675. https://doi.org/10.1172/JCI13202.
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Article

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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Figure 7

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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).