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Open AccessArticle

TNF-α in Combination with Palmitate Enhances IL-8 Production via The MyD88- Independent TLR4 Signaling Pathway: Potential Relevance to Metabolic Inflammation

1
Microbiology & Immunology Department, Dasman Diabetes Institute, Kuwait City 15462, Kuwait
2
Medical Division, Dasman Diabetes Institute, Kuwait City 15462, Kuwait
3
Genetics and Bioinformatics, Dasman Diabetes Institute, Kuwait City 15462, Kuwait
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2019, 20(17), 4112; https://doi.org/10.3390/ijms20174112
Received: 28 July 2019 / Revised: 16 August 2019 / Accepted: 17 August 2019 / Published: 23 August 2019
(This article belongs to the Special Issue Nutrition, Brown and White Adipose Tissue 2.0)
Elevated levels of IL-8 (CXCL8) in obesity have been linked with insulin resistance and type 2 diabetes (T2D). The mechanisms that lead to the profound production of IL-8 in obesity remains to be understood. TNF-α and saturated free fatty acids (FFAs) are increased in obese humans and correlate with insulin resistance. Hence, we sought to investigate whether the cooccurrence of TNF-α and FFAs led to increase the production of IL-8 by human monocytes. We found that co-stimulation of human monocytes with palmitate and TNF-α led to increased IL-8 production as compared to those stimulated with palmitate or TNF-α alone. The synergistic production of IL-8 by TNF-α/palmitate was suppressed by neutralizing anti- Toll like receptor 4 (TLR4) antibody and by genetic silencing of TLR4. Both MyD88-deficient and MyD88-competent cells responded comparably to TNF-α/Palmitate. However, TIR-domain-containing adapter-inducing interferon (TRIF) inhibition or interferon regulatory transcription factor 3 (IRF3) knockdown partly blocked the synergistic production of IL-8. Our human data show that increased adipose tissue TNF-α expression correlated positively with IL-8 expression (r = 0.49, P = 0.001). IL-8 and TNF-α correlated positively with macrophage markers including CD68, CD163 and CD86 in adipose tissue. These findings suggest that the signaling cross-talk between saturated fatty acid palmitate and TNF-α may be a key driver in obesity-associated chronic inflammation via an excessive production of IL-8. View Full-Text
Keywords: inflammation; interleukin-8; tumor necrosis factor-alpha; free fatty acids; toll-like receptor 4 inflammation; interleukin-8; tumor necrosis factor-alpha; free fatty acids; toll-like receptor 4
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Hasan, A.; Akhter, N.; Al-Roub, A.; Thomas, R.; Kochumon, S.; Wilson, A.; Koshy, M.; Al-Ozairi, E.; Al-Mulla, F.; Ahmad, R. TNF-α in Combination with Palmitate Enhances IL-8 Production via The MyD88- Independent TLR4 Signaling Pathway: Potential Relevance to Metabolic Inflammation. Int. J. Mol. Sci. 2019, 20, 4112.

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