Dataset Information

Stearic Acid and TNF-? Co-Operatively Potentiate MIP-1? Production in Monocytic Cells via MyD88 Independent TLR4/TBK/IRF3 Signaling Pathway.

ABSTRACT: Increased circulatory and adipose tissue expression of macrophage inflammatory protein (MIP)-1? (CC motif chemokine ligand-3/CCL3) and its association with inflammation in the state of obesity is well documented. Since obesity is associated with increases in both stearic acid and tumor necrosis factor ? (TNF-?) in circulation, we investigated whether stearic acid and TNF-? together could regulate MIP-1?/CCL3 expression in human monocytic cells, and if so, which signaling pathways were involved in MIP-1?/CCL3 modulation. Monocytic cells were treated with stearic acid and TNF-? resulted in enhanced production of MIP-1?/CCL3 compared to stearic acid or TNF-? alone. To explore the underlying mechanisms, cooperative effect of stearic acid for MIP-?/CCL3 expression was reduced by TLR4 blocking, and unexpectedly we found that the synergistic production of MIP-?/CCL3 in MyD88 knockout (KO) cells was not suppressed. In contrast, this MIP-?/CCL3 expression was attenuated by inhibiting TBK1/IRF3 activity. Cells deficient in IRF3 did not show cooperative effect of stearate/TNF-? on MIP-1?/CCL3 production. Furthermore, activation of IRF3 by polyinosinic-polycytidylic acid (poly I:C) produced a cooperative effect with TNF-? for MIP-1?/CCL3 production that was comparable to stearic acid. Individuals with obesity show high IRF3 expression in monocytes as compared to lean individuals. Furthermore, elevated levels of MIP-1?/CCL3 positively correlate with TNF-? and CD163 in fat tissues from individuals with obesity. Taken together, this study provides a novel model for the pathologic role of stearic acid to produce MIP-1?/CCL3 in the presence of TNF-? associated with obesity settings.

SUBMITTER: Kochumon S

PROVIDER: S-EPMC7600458 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Stearic Acid and TNF-α Co-Operatively Potentiate MIP-1α Production in Monocytic Cells via MyD88 Independent TLR4/TBK/IRF3 Signaling Pathway.

Kochumon Shihab S Arefanian Hossein H Azim Rafaat R Shenouda Steve S Jacob Texy T Abu Khalaf Nermeen N Al-Rashed Fatema F Hasan Amal A Sindhu Sardar S Al-Mulla Fahd F Ahmad Rasheed R

Biomedicines 20201009 10

Increased circulatory and adipose tissue expression of macrophage inflammatory protein (MIP)-1α (CC motif chemokine ligand-3/CCL3) and its association with inflammation in the state of obesity is well documented. Since obesity is associated with increases in both stearic acid and tumor necrosis factor α (TNF-α) in circulation, we investigated whether stearic acid and TNF-α together could regulate MIP-1α/CCL3 expression in human monocytic cells, and if so, which signaling pathways were involved i ...[more]

PMID: 33050324

Similar Datasets

Project description:Metabolic inflammation is associated with increased expression of saturated free fatty acids, proinflammatory cytokines, chemokines, and adipose oxidative stress. Macrophage inflammatory protein (MIP)-1? recruits the inflammatory cells such as monocytes, macrophages, and neutrophils in the adipose tissue; however, the mechanisms promoting the MIP-1? expression remain unclear. We hypothesized that MIP-1? co-induced by palmitate and tumor necrosis factor (TNF)-? in monocytic cells/macrophages could be further enhanced in the presence of reactive oxygen species (ROS)-mediated oxidative stress. To investigate this, THP-1 monocytic cells and primary human macrophages were co-stimulated with palmitate and TNF-? and mRNA and protein levels of MIP-1? were measured by using quantitative reverse transcription, polymerase chain reaction (qRT-PCR) and commercial enzyme-linked immunosorbent assays (ELISA), respectively. The cognate receptor of palmitate, toll-like receptor (TLR)-4, was blunted by genetic ablation, neutralization, and chemical inhibition. The involvement of TLR4-downstream pathways, interferon regulatory factor (IRF)-3 or myeloid differentiation (MyD)-88 factor, was determined using IRF3-siRNA or MyD88-deficient cells. Oxidative stress was induced in cells by hydrogen peroxide (H2O2) treatment and ROS induction was measured by dichloro-dihydro-fluorescein diacetate (DCFH-DA) assay. The data show that MIP-1? gene/protein expression was upregulated in cells co-stimulated with palmitate/TNF-? compared to those stimulated with either palmitate or TNF-? (P < 0.05). Further, TLR4-IRF3 pathway was implicated in the cooperative induction of MIP-1? in THP-1 cells, and this cooperativity between palmitate and TNF-? was clathrin-dependent and also required signaling through c-Jun and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-?B). Notably, ROS itself induced MIP-1? and could further promote MIP-1? secretion together with palmitate and TNF-?. In conclusion, palmitate and TNF-? co-induce MIP-1? in human monocytic cells via the TLR4-IRF3 pathway and signaling involving c-Jun/NF-?B. Importantly, oxidative stress leads to ROS-driven MIP-1? amplification, which may have significance for metabolic inflammation.

Dataset Information

Stearic Acid and TNF-? Co-Operatively Potentiate MIP-1? Production in Monocytic Cells via MyD88 Independent TLR4/TBK/IRF3 Signaling Pathway.

Publications

Stearic Acid and TNF-α Co-Operatively Potentiate MIP-1α Production in Monocytic Cells via MyD88 Independent TLR4/TBK/IRF3 Signaling Pathway.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets