Abstract
Metabolic inflammation is associated with increased expression of saturated free fatty acids, proinflammatory cytokines, chemokines, and adipose oxidative stress. Macrophage inflammatory protein (MIP)-1α recruits the inflammatory cells such as monocytes, macrophages, and neutrophils in the adipose tissue; however, the mechanisms promoting the MIP-1α expression remain unclear. We hypothesized that MIP-1α co-induced by palmitate and tumor necrosis factor (TNF)-α 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-α and mRNA and protein levels of MIP-1α 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-1α gene/protein expression was upregulated in cells co-stimulated with palmitate/TNF-α compared to those stimulated with either palmitate or TNF-α (P < 0.05). Further, TLR4-IRF3 pathway was implicated in the cooperative induction of MIP-1α in THP-1 cells, and this cooperativity between palmitate and TNF-α was clathrin-dependent and also required signaling through c-Jun and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). Notably, ROS itself induced MIP-1α and could further promote MIP-1α secretion together with palmitate and TNF-α. In conclusion, palmitate and TNF-α co-induce MIP-1α in human monocytic cells via the TLR4-IRF3 pathway and signaling involving c-Jun/NF-κB. Importantly, oxidative stress leads to ROS-driven MIP-1α amplification, which may have significance for metabolic inflammation.
Highlights
Metabolic inflammation in obesity is associated with multiple factors such as oxidative stress, proinflammatory cytokines/chemokines, adipokines, and free fatty acids
We asked if palmitate and tumor necrosis factor (TNF)-α could co-induce Macrophage inflammatory protein (MIP)-1α expression in THP-1 human monocytic cells and primary human macrophages
TNF-α, and MIP-1α have emerged as critical players in metabolic
Summary
Metabolic inflammation in obesity is associated with multiple factors such as oxidative stress, proinflammatory cytokines/chemokines, adipokines, and free fatty acids. Activated monocytes and M1 macrophages secrete proinflammatory cytokines and chemokines including tumor necrosis factor (TNF)-α, IL-1β, IL-6, and α/β chemokines [2]. MIPs are important players in the induction of other proinflammatory cytokines such as TNF-α, IL-1β, and IL-6 in activated macrophages and fibroblasts; while, through their stimulatory effects on granulocytes, MIPs can induce acute neutrophilic inflammation [6]. MIP-1α is a major chemoattractant for monocytes/macrophages, T-lymphocytes and neutrophils [7]. It is produced by several activated cells including monocytes, macrophages, CD8+ T lymphocytes, dendritic cells, endothelial cells, fibroblasts, and microglial cells [8]. MIP-1α is involved in the pathogenesis of many chronic inflammatory conditions such as rheumatoid arthritis, multiple myeloma, leukemogenesis, periodontitis, and Sjögren syndrome [9,10]
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