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Open AccessArticle

The Cooperative Induction of CCL4 in Human Monocytic Cells by TNF-α and Palmitate Requires MyD88 and Involves MAPK/NF-κB Signaling Pathways

1
Animal and Imaging Core Facility, Dasman Diabetes Institute, Dasman 15462, Kuwait, [email protected]
2
Microbiolgy and Immunology, Dasman Diabetes Institute, Dasman 15462, Kuwait, [email protected] (S.K.)
3
Genetics & Bioinformatics, Dasman Diabetes Institute, Dasman 15462, Kuwait, [email protected]
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Int. J. Mol. Sci. 2019, 20(18), 4658; https://doi.org/10.3390/ijms20184658
Received: 23 July 2019 / Revised: 15 September 2019 / Accepted: 17 September 2019 / Published: 19 September 2019
(This article belongs to the Special Issue Molecular Research on Metabolic Disorders)
Chronic low-grade inflammation, also known as metabolic inflammation, is a hallmark of obesity and parallels with the presence of elevated circulatory levels of free fatty acids and inflammatory cytokines/chemokines. CCL4/MIP-1β chemokine plays a key role in the adipose tissue monocyte recruitment. Increased circulatory levels of TNF-α, palmitate and CCL4 are co-expressed in obesity. We asked if the TNF-α/palmitate could interact cooperatively to augment the CCL4 production in human monocytic cells and macrophages. THP-1 cells/primary macrophages were co-treated with TNF-α/palmitate and CCL4 mRNA/protein expression was assessed using qRT-PCR/ELISA. TLR4 siRNA, a TLR4 receptor-blocking antibody, XBlue™-defMyD cells and pathway inhibitors were used to decipher the signaling mechanisms. We found that TNF-α/palmitate co-stimulation augmented the CCL4 expression in monocytic cells and macrophages compared to controls (p < 0.05). TLR4 suppression or neutralization abrogated the CCL4 expression in monocytic cells. Notably, CCL4 cooperative induction in monocytic cells was: (1) Markedly less in MyD88-deficient cells, (2) IRF3 independent, (3) clathrin dependent and (4) associated with the signaling mechanism involving ERK1/2, c-Jun, JNK and NF-κB. In conclusion, TNF-α/palmitate co-stimulation promotes the CCL4 expression in human monocytic cells through the mechanism involving a TLR4-MyD88 axis and MAPK/NF-κB pathways. These findings unravel a novel mechanism of the cooperative induction of CCL4 by TNF-α and palmitate which could be relevant to metabolic inflammation. View Full-Text
Keywords: CCL4; MIP-1β; TNF-α; palmitate; TLR4; MyD88; MAPK; NF-κB CCL4; MIP-1β; TNF-α; palmitate; TLR4; MyD88; MAPK; NF-κB
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Sindhu, S.; Kochumon, S.; Shenouda, S.; Wilson, A.; Al-Mulla, F.; Ahmad, R. The Cooperative Induction of CCL4 in Human Monocytic Cells by TNF-α and Palmitate Requires MyD88 and Involves MAPK/NF-κB Signaling Pathways. Int. J. Mol. Sci. 2019, 20, 4658.

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