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.