Circulating IL-6 contributes to peripheral LPS-induced mPGES-1 expression in the rat brain

Interleukin-(IL)6 is the most prominent circulating cytokine induced by systemic infection and inflammation, and the main humoral mediator to the brain in fever. We have previously demonstrated that the PG-pathway, the ultimate step in fever generation, is activated by circulating IL-6 by triggering the expression of the rate limiting enzyme cyclooxygenase (COX)2 in the brain. Downstream of COX2, another enzyme, microsomal PG synthase (mPGES)-1 has also been implicated in the inflammatory response but relatively little is known about its role in cytokine mediated inflammation. Here, we investigated for the first time the direct role of circulating IL-6 in brain and peripheral mPGES-1-expression. Rats were either treated with LPS into a subcutaneous air pouch combined with intraperitoneal injection of a rat specific IL-6 antiserum (AS) or received a single intraperitoneal injection of IL-6. LPS increased the expression of mPGES-1 mRNA in the brain, liver and brown adipose tissue (BAT) but not epididymal white (eW) adipose tissue. This response was reversed by IL-6AS in LPS-injected animals for the brain and liver. IL-6-treatment only induced mPGES-1-expression in the brain and its immunoreactivity co-localized with phosphorylated signal transducer and activator of transcription (STAT)3 the main transcription factor activated by IL-6. Moreover, circulating IL-6 levels and the suppressor of cytokine signaling (SOCS)-3, a broadly used marker of STAT3-activation, strongly correlated with mPGES-1 expression in the brain. In summary, we have clearly shown that circulating IL-6 can directly induce mPGES-1 linked to STAT3-activation in the brain but not peripheral tissues of rats during localised peripheral inflammation.