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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The cell viability as well as the proportion of dead/dying cells are dif...
The cell viability as well as the proportion of dead/dying cells are different between PPARγ+/+ and PPARγ+/– mice, whereas the addition of PPARγ agonists did not alter those parameters, except 5 μM of 15d-PGJ2. The B cells from PPARγ+/+ (a) or PPARγ+/– (b) are cultured in the absence or presence of PPARγ agonists and their viable cell number were counted by trypan blue exclusion. The percentage of dead or dying cells of B cells from PPARγ+/+ (c) or PPARγ+/– (d) in the culture were counted by PI staining. B cells were cultured without agonist (closed squares), or with troglitazone 20 μM (filled circles), troglitazone 50 μM (filled triangles), 15d-PGJ2 2 μM (filled diamonds), and 15d-PGJ2 5 μM (open squares). *P < 0.05 for the cell number or percentage of dead cells compared to those in the absence of the agonist.