Stearic acid and tnf-α co-operatively potentiate mip-1α production in monocytic cells via myd88 independent tlr4/tbk/irf3 signaling pathway

Shihab Kochumon, Hossein Arefanian, Rafaat Azim, Steve Shenouda, Texy Jacob, Nermeen Abu Khalaf, Fatema Al-Rashed, Amal Hasan, Sardar Sindhu, Fahd Al-Mulla, Rasheed Ahmad

Research output: Contribution to journalArticlepeer-review

Abstract

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 in MIP-1α/CCL3 modulation. Monocytic cells were treated with stearic acid and TNF-α resulted in enhanced production of MIP-1α/CCL3 compared to stearic acid or TNF-α alone. To explore the underlying mechanisms, cooperative effect of stearic acid for MIP-α/CCL3 expression was reduced by TLR4 blocking, and unexpectedly we found that the synergistic production of MIP-α/CCL3 in MyD88 knockout (KO) cells was not suppressed. In contrast, this MIP-α/CCL3 expression was attenuated by inhibiting TBK1/IRF3 activity. Cells deficient in IRF3 did not show cooperative effect of stearate/TNF-α on MIP-1α/CCL3 production. Furthermore, activation of IRF3 by polyinosinic-polycytidylic acid (poly I:C) produced a cooperative effect with TNF-α for MIP-1α/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-1α/CCL3 positively correlate with TNF-α 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-1α/CCL3 in the presence of TNF-α associated with obesity settings.

Original languageEnglish
Article number403
Pages (from-to)1-16
Number of pages16
JournalBiomedicines
Volume8
Issue number10
DOIs
Publication statusPublished - Oct 2020

Keywords

  • IRF3
  • MIP-1α
  • Obesity
  • Stearic acid
  • TLR4
  • TNF-α/CCL3
  • TRIF/TBK

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