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.
Highlights
The incidence of obesity is growing worldwide
We asked whether stearic acid has a cooperative effect on tumor necrosis factor α (TNF-α) mediated macrophage inflammatory protein (MIP)-1α/CCL3 production in monocytic cells
We found that cotreatment of TNF-α and stearic acid synergize the MIP-1α/CCL3 gene expression in monocytic cells (THP-1 cells and primary human monocytes) compared to cells treated with either TNF-α or stearic acid alone. (Figure 1A)
Summary
The incidence of obesity is growing worldwide. The presence of obesity leads to the development of chronic inflammation, which is critical in the pathogenesis of insulin resistance and metabolic syndrome [1]. Besides cytokines/chemokines produced by immune cells in adipose tissue, adipocyte-driven metabolites such as saturated free fatty acids (FFAs) are potent mediators of chronic inflammation and insulin resistance in obesity [8]. Palmitic acid is a stimulator of toll-like receptor 4 (TLR4) signaling pathways in monocytes/macrophages and contributes to obesity-related chronic inflammation and insulin resistance [10]. Stearic acid role in the regulation of inflammatory responses in monocytic cells is poorly studied In both humans and rodents, the accumulation of monocytes/macrophages into the adipose tissue correlates with the development of obesity and insulin resistance [3]. As higher levels of stearic acid and TNF-α have been observed in the circulation of obese/type 2 diabetic individuals, we asked whether stearic acid and TNF-α could cooperatively enhance the MIP-1α/CCL3 production in monocytic cells and adipocytes.
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