Abstract
Elevated levels of IL-8 (CXCL8) in obesity have been linked with insulin resistance and type 2 diabetes (T2D). The mechanisms that lead to the profound production of IL-8 in obesity remains to be understood. TNF-α and saturated free fatty acids (FFAs) are increased in obese humans and correlate with insulin resistance. Hence, we sought to investigate whether the cooccurrence of TNF-α and FFAs led to increase the production of IL-8 by human monocytes. We found that co-stimulation of human monocytes with palmitate and TNF-α led to increased IL-8 production as compared to those stimulated with palmitate or TNF-α alone. The synergistic production of IL-8 by TNF-α/palmitate was suppressed by neutralizing anti- Toll like receptor 4 (TLR4) antibody and by genetic silencing of TLR4. Both MyD88-deficient and MyD88-competent cells responded comparably to TNF-α/Palmitate. However, TIR-domain-containing adapter-inducing interferon (TRIF) inhibition or interferon regulatory transcription factor 3 (IRF3) knockdown partly blocked the synergistic production of IL-8. Our human data show that increased adipose tissue TNF-α expression correlated positively with IL-8 expression (r = 0.49, P = 0.001). IL-8 and TNF-α correlated positively with macrophage markers including CD68, CD163 and CD86 in adipose tissue. These findings suggest that the signaling cross-talk between saturated fatty acid palmitate and TNF-α may be a key driver in obesity-associated chronic inflammation via an excessive production of IL-8.
Highlights
Obesity-mediated low-grade chronic inflammation plays a key role in the development of various diseases including Type 2 diabetes, atherosclerosis, and hepatic steatosis
IL-8 gene expression and protein secretion were significantly higher in monocytes cotreated with palmitate and tumor necrosis factor-α (TNF-α) compared to cells treated with palmitate or TNF-α alone (Figure 1A,B; Supplemental Figure S1A,B)
Since the anti-inflammatory role of short chain fatty acids (SCFAs) such as butyrate, propionate, and acetate is well documented [39,40], we assessed whether one such SCFA, namely propionate, synergizes with TNF-α for IL-8 production
Summary
Obesity-mediated low-grade chronic inflammation plays a key role in the development of various diseases including Type 2 diabetes, atherosclerosis, and hepatic steatosis. Pro-inflammatory macrophage accumulation in adipose tissue is an important feature of obesity, correlating with local expression of inflammatory markers including tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-1β (IL-1β) and C-C Motif Chemokine Ligand 2 (CCL2) [1,2,3,4] These inflammatory mediators contribute to the infiltration of circulatory monocytes into the adipose tissue which play a central role in the development and maintenance of obesity-associated chronic low-grade inflammation [5,6]. This inflammatory stimulation creates a vicious circle of IL-8 production in human adipocytes via extracellular signal-regulated kinases (ERK) pathway and/or p38 mitogen-activated protein kinase (MAPK) pathway [28] These findings indicate that IL-8 plays a critical role in both the initiation and maintenance of inflammation in the adipose tissue. IL-8 and TNF- α correlated positively with macrophage markers including CD68, CD163 and CD86 in adipose tissue
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