Enhanced Palmitate-Induced Interleukin-8 Formation in Human Macrophages by Insulin or Prostaglandin E2

Abstract

Macrophages in pathologically expanded dysfunctional white adipose tissue are exposed to a mix of potential modulators of inflammatory response, including fatty acids released from insulin-resistant adipocytes, increased levels of insulin produced to compensate insulin resistance, and prostaglandin E2 (PGE2) released from activated macrophages. The current study addressed the question of how palmitate might interact with insulin or PGE2 to induce the formation of the chemotactic pro-inflammatory cytokine interleukin-8 (IL-8). Human THP-1 cells were differentiated into macrophages. In these macrophages, palmitate induced IL-8 formation. Insulin enhanced the induction of IL-8 formation by palmitate as well as the palmitate-dependent stimulation of PGE2 synthesis. PGE2 in turn elicited IL-8 formation on its own and enhanced the induction of IL-8 release by palmitate, most likely by activating the EP4 receptor. Since IL-8 causes insulin resistance and fosters inflammation, the increase in palmitate-induced IL-8 formation that is caused by hyperinsulinemia and locally produced PGE2 in chronically inflamed adipose tissue might favor disease progression in a vicious feed-forward cycle.

Improvement in insulin sensitivity and prevention of high fat diet-induced liver pathology using a CXCR2 antagonist

“…For example, previous studies have shown a CXCR2 mediated inhibitory effect on insulin-induced glucose transport in muscle cells mediated by activation of the JAK/STAT pathway and stimulation of the expression of SOCS-2, a known insulin receptor inhibitor [ 56 ]. In addition, scientific evidence highlights IL-8 as a main adipocytokine producing insulin resistance via the inhibition of insulin-induced Akt phosphorylation in adipocytes [ 57 , 58 ]. Furthermore, very recent data highlighted a specific role of CXCR2 expressed in adipocytes in the modulation of murine adipocyte response to high glucose concentration and shed light on its role in the regulation of the proinflammatory response and insulin sensitivity [ 59 ].…”

“…While CXCR2 antagonism prevents the accumulation of neutrophils inside inflamed liver, its effects on metabolic activity are very likely to contribute, independently of effects on neutrophils, to the effects we observed in this study. The expression of CXCR2 on insulin-responsive muscle and adipose indicates that AZD5069 could be acting on these tissues, concomitant with actions on neutrophils, as CXCR2 activation in muscle and adipose results in impaired insulin-induced glucose transport [ 56 ] and insulin resistance [ 57 , 58 ].…”

Macrophages, Low-Grade Inflammation, Insulin Resistance and Hyperinsulinemia: A Mutual Ambiguous Relationship in the Development of Metabolic Diseases

“…Other arachidonic acid-derived lipid mediators such as PGE 2 produced in Kupffer cells and infiltrating macrophages in insulin-resistant livers plays an ambiguous role in the development of insulin resistance. While PGE 2 can enhance the production by macrophages of a number of pro-inflammatory cytokines that cause insulin resistance [ 151 , 152 ], enhance the cytokine-induced insulin resistance in hepatocytes [ 153 ] and thereby contribute to the development of insulin resistance, it inhibits the production of TNFα in macrophages [ 154 ]. In vivo, the PGE 2 -dependent inhibition of the TNFα formation appears to outweigh the stimulation of other pro-inflammatory cytokines, because attenuation of diet-induced PGE 2 formation by genetic deletion of the microsomal PGE synthase 1 (mPGES-1), a key enzyme in the synthesis of PGE 2 , enhanced the relative insulin resistance index in comparison to wildtype animals receiving the same diet [ 146 ].…”

“…The insulin-dependent increase in cytokine production possibly was mediated in part by eliciting a prostaglandin E 2 -dependent positive autocrine feed-forward loop. Similarly, both insulin and prostaglandin E 2 enhanced the palmitate-dependent IL-8 formation in THP-1 macrophages [ 152 ]. Similar results were found for the chemokine CCL2 (Klauder et al, unpublished results).…”

Macrophages in Health and Non-Infectious Disease 2.0

“…There was increased production of interleukin-8 and prostaglandin E 2 in THP-1-derived macrophages after palmitate treatment, and insulin enhanced these effects, suggesting the role of palmitate in the progression of inflammation in adipose tissues [ 17 ].…”