Effect of PPARalpha activation of macrophages on the secretion of inflammatory cytokines in cultured adipocytes

Kentaro Murakami, Hideaki Bujo, Hiroyuki Unoki, Yasushi Saito
European Journal of Pharmacology 2007 April 30, 561 (1): 206-13
The relationship between adipocytes and infiltrated macrophages in fat tissue is important for the pathogenesis of insulin resistance through the activation of cytokines. Peroxisome proliferator-activated receptors (PPARs) play a role in the regulation of cytokine secretion in these cells. We studied the effect of the PPARalpha activation of macrophages on the modulation of the tumor necrosis factor alpha (TNFalpha) expression in adipocytes using a cell culture system. A conditioned medium of lipopolysaccharide (LPS)-stimulated RAW264.7 cells, a macrophage cell line, induced the level of TNFalpha mRNA in 3T3-L1 adipocytes. This effect was inhibited by the addition of neutralizing antibody against interleukin 6 (IL-6) in the conditioned medium or the preincubation of RAW264.7 cells with a specific PPARalpha agonist, K-111 (2,2-dichloro-12-(4-chlorophenyl)dodecanoic acid). K-111 reduced both the IL-6 production and mRNA expression in RAW264.7 cells, and its effect was stronger than that of rosiglitazone, a PPARgamma agonist. The activation of the stress-activated protein kinase/c-Jun NH2-terminal kinase (SAPK/JNK) pathway and nuclear factor kappa B (NF-kappaB) subunits of p65 was significantly inhibited by K-111. The blocking of IL-6 production through the SAPK/JNK pathway or by transfection with siRNA specific for IL-6 abolished the inhibitory effect of K-111 on the TNFalpha expression in the 3T3-L1 adipocytes. As a result, the IL-6 produced by RAW264.7 cells is an inducer of TNFalpha expression in 3T3-L1 adipocytes, and the IL-6 secretion is inhibited by the activation of PPARalpha. The PPARalpha activators may suppress the pathogenetical secretion of TNFalpha in the adipocytes through the functional modulation of the infiltrated macrophages.

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