MIP-1α Induction by Palmitate in the Human Monocytic Cells Implicates TLR4 Signaling Mechanism

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Abstract

Background/Aims: MIP-1α (macrophage inflammatory protein 1α)/CCL3 chemokine is associated with the adipose tissue inflammation in obesity. Both MIP-1α and free fatty acids are elevated in obesity/T2D. We asked if free fatty acid palmitate could modulate MIP-1α expression in the human monocytic cells. Methods: Human monocytic THP-1 cells and macrophages were stimulated with palmitate and TNF-α (positive control). MIP-1α expression was measured with real time RT-PCR, Flow Cytometry and ELISA. Signaling pathways were identified by using THP-1-XBlue™ cells, THP-1-XBlue™-defMyD cells, anti-TLR4 mAb and TLR4 siRNA. Results: Our data show that palmitate induced significant increase in MIP-1α production in monocytic THP-1 cells/macrophages. MIP-1α induction was significantly suppressed when cells were treated with anti-TLR4 antibody prior stimulation with palmitate. Using TLR4 siRNA, we further demonstrate that palmitate-induced MIP-1α expression in monocytic cells requires TLR4. Moreover, THP1 cells defective in MyD88, a major adaptor protein involved in TLR4 signaling, were unable to induce MIP-1α production in response to palmitate. Palmitate-induced MIP-1α expression was suppressed by inhibition of MAPK, NF-kB and PI3K signaling pathways. In addition, palmitate-induced NF-kB/AP-1 activation was observed while production of MIP-1α. However, this activation of NF-kB/AP-1 was abrogated in MyD88 deficient cells. Conclusion: Overall, these results show that palmitate induces TLR4-dependent MIP-1α expression requiring the MyD88 recruitment and activation of MAPK, NF-kB/AP-1 and PI3K signaling. It implies that the increased systemic levels of free fatty acid palmitate in obesity/T2D may contribute to metabolic inflammation through excessive production of MIP-1α.

Original languageEnglish
Pages (from-to)212-224
Number of pages13
JournalCellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology
Volume52
Issue number2
DOIs
Publication statusPublished - 1 Jan 2019

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Keywords

  • Adaptor Proteins, Signal Transducing/genetics
  • Diabetes Mellitus, Type 2/genetics
  • Humans
  • MAP Kinase Signaling System/drug effects
  • Macrophages/metabolism
  • Monocytes/metabolism
  • Myeloid Differentiation Factor 88/genetics
  • Obesity/genetics
  • Palmitic Acid/pharmacology
  • THP-1 Cells
  • Toll-Like Receptor 4/genetics

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