Interleukin-6 and interleukin-15 are selectively regulated by lipopolysaccharide and interferon-γ in primary pig adipocytes

Abstract

3T3-L1 adipocytes express the lipopolysaccharide (LPS) receptor and respond to direct stimulation with the antigen by increasing the expression of inflammatory mediators. Activation of this receptor by its ligand in the macrophage causes the activation and translocation of nuclear factor-kappaB (NF-kappaB) to the nucleus where it regulates the expression of proinflammatory cytokines and other target genes. We investigated whether LPS could stimulate NF-kappaB translocation in primary pig adipocytes and regulate the expression and secretion of TNF-alpha and IL-6. LPS clearly induced the nuclear translocation of NF-kappaB and also upregulated (P < 0.05) the mRNA expression and secretion of IL-6 into the culture medium. An induction of TNF-alpha expression by LPS was not detected, but with extended incubation (8 h), there was a modest increase (P < 0.09) in the media concentration of this cytokine. Inhibition of either ERK1/2, PKC, or the inhibitory G protein (Gi) with U-0126, bisindolylmaleimide HCl, and pertussis toxin, respectively, blocked (P < 0.05) the increase in IL-6 expression caused by LPS. Because LPS administration in vivo increases circulating concentrations of IFN-gamma, and because this cytokine also regulates multiple immune modulators in the adipocyte, we also determined whether IFN-gamma regulates cytokine expression in primary adipocytes. Although the expression of IL-6 and TNF-alpha was unresponsive to IFN-gamma, the expression of IL-15 was markedly upregulated (P < 0.01). Furthermore, the induction of IL-15 expression by IFN-gamma was blocked by inhibition of PKC. These data indicate that NF-kappaB is responsive to LPS in the adipocyte and also identify key mediators of LPS-induced IL-6 expression. In addition, we provide novel evidence that IFN-gamma targets the adipocyte to induce IL-15 expression, thus indicating a possible role for the adipocyte in the regulation of T-cell function and muscle metabolism during the innate immune response.

IL-15 concentrations in skeletal muscle and subcutaneous adipose tissue in lean and obese humans: local effects of IL-15 on adipose tissue lipolysis

“…Based on the magnitude of difference between SCAT and plasma IL-15, suppositions that IL-15 would reach adipose tissue from the circulation, operating as an endocrine mediator of body composition, do not seem likely. We contend that an autocrine/paracrine IL-15 axis (IL-15 released in adipose tissue acting in adipose tissue) is more likely to exist than the proposed SkM-blood-adipose tissue IL-15 axis, in line with a similar model identified in porcine adipocytes (1,2). However, because the positive resting correlation between SCAT IL-15 and SCAT glycerol is not causal, it is very possible that IL-15 may not play a substantial role in regulating basal lipolysis in human adipose tissue.…”

“…Conversely, obese SkM IL-15 mRNA expression was not related to plasma IL-15 (21), indicating that SkM may not contribute substantially to systemic IL-15. Evidence that adipocytes express IL-15 (1,29) and that obesity is considered a low-grade inflammatory condition (9) suggests that adipose tissue in obese humans may express/secrete more IL-15 than adipose tissue in lean individuals. To our knowledge, no studies have assessed human adipose tissue IL-15 concentrations, leaving the endocrine and autocrine/paracrine metabolic roles of IL-15 in human obesity unanswered.…”

Anti-Interleukin-15 Prevents Arthritis inBorrelia-Vaccinated and -Infected Mice

“…If proinflammatory cytokines are detected, the vaccine could be modified to remove epitopes that promote adverse effects but do not influence the ability of the vaccine to induce protection. Finally, several investigators (2,31,40) have shown that gamma interferon can up-regulate the production of IL-15. This suggests that gamma interferon may precede IL-15 in the cytokine cascade for the modulation of arthritis associated with Borrelia vaccination and challenge.…”

TLR4 links innate immunity and fatty acid–induced insulin resistance

“…After lipid infusion, adipose tissue was collected for EMSA analysis. Adipose tissue nuclear extracts were prepared as previously described (44). The consensus NF-κB oligonucleotides (Promega) were end-labeled with [γ-32 P]ATP (PerkinElmer) using T4 polynucleotide kinase (Promega).…”