| RRC ID |
88284
|
| 著者 |
Ahmad R, Al-Roub A, Kochumon S, Akther N, Thomas R, Kumari M, Koshy MS, Tiss A, Hannun YA, Tuomilehto J, Sindhu S, Rosen ED.
|
| タイトル |
The Synergy between Palmitate and TNF-α for CCL2 Production Is Dependent on the TRIF/IRF3 Pathway: Implications for Metabolic Inflammation.
|
| ジャーナル |
J Immunol
|
| Abstract |
The chemokine CCL2 (also known as MCP-1) is a key regulator of monocyte infiltration into adipose tissue, which plays a central role in the pathophysiology of obesity-associated inflammation and insulin resistance. It remains unclear how CCL2 production is upregulated in obese humans and rodents. Because elevated levels of the free fatty acid (FFA) palmitate and TNF-α have been reported in obesity, we studied whether these agents interact to trigger CCL2 production. Our data show that treatment of THP-1 and primary human monocytic cells with palmitate and TNF-α led to a marked increase in CCL2 production compared with either treatment alone. Mechanistically, we found that cooperative production of CCL2 by palmitate and TNF-α did not require MyD88, but it was attenuated by blocking TLR4 or TRIF. IRF3-deficient cells did not show synergistic CCL2 production in response to palmitate/TNF-α. Moreover, IRF3 activation by polyinosinic-polycytidylic acid augmented TNF-α-induced CCL2 secretion. Interestingly, elevated NF-κB/AP-1 activity resulting from palmitate/TNF-α costimulation was attenuated by TRIF/IRF3 inhibition. Diet-induced C57BL/6 obese mice with high FFAs levels showed a strong correlation between TNF-α and CCL2 in plasma and adipose tissue and, as expected, also showed increased adipose tissue macrophage accumulation compared with lean mice. Similar results were observed in the adipose tissue samples from obese humans. Overall, our findings support a model in which elevated FFAs in obesity create a milieu for TNF-α to trigger CCL2 production via the TLR4/TRIF/IRF3 signaling cascade, representing a potential contribution of FFAs to metabolic inflammation.
|
| 巻・号 |
200(10)
|
| ページ |
3599-3611
|
| 公開日 |
2018-5-15
|
| DOI |
10.4049/jimmunol.1701552
|
| PII |
jimmunol.1701552
|
| PMID |
29632147
|
| PMC |
PMC5937214
|
| MeSH |
Adaptor Proteins, Vesicular Transport / metabolism*
Adipose Tissue / drug effects
Adipose Tissue / metabolism
Animals
Cell Line
Chemokine CCL2 / metabolism*
Humans
Inflammation / drug therapy*
Inflammation / metabolism*
Insulin Resistance / physiology
Interferon Regulatory Factor-3 / metabolism*
Macrophages / drug effects
Macrophages / metabolism
Mice
Mice, Inbred C57BL
Monocytes / drug effects
Monocytes / metabolism
Myeloid Differentiation Factor 88 / metabolism
NF-kappa B / metabolism
Palmitates / pharmacology*
Signal Transduction / drug effects
Toll-Like Receptor 4 / metabolism
Tumor Necrosis Factor-alpha / pharmacology*
|
| IF |
4.886
|
| リソース情報 |
| 実験動物マウス |
RBRC00858 |
