| Summary: | 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 E<sub>2</sub> (PGE<sub>2</sub>) released from activated macrophages. The current study addressed the question of how palmitate might interact with insulin or PGE<sub>2</sub> 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 PGE<sub>2</sub> synthesis. PGE<sub>2</sub> 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 PGE<sub>2</sub> in chronically inflamed adipose tissue might favor disease progression in a vicious feed-forward cycle.
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