INTERLEUKIN (IL) 1-BETA, IL-1 RECEPTOR ANTAGONIST, IL-10, AND IL-13 GENE-EXPRESSION IN THE CENTRAL-NERVOUS-SYSTEM AND ANTERIOR-PITUITARY DURING SYSTEMIC INFLAMMATION - PATHOPHYSIOLOGICAL IMPLICATIONS

The pathophysiology of systemic inflammation and sepsis involves perip heral organs, causing gastrointestinal, renal, and cardiovascular alte rations, as well as the central nervous system (CNS), affecting sleep, temperature regulation, behavior, and neuroendocrine function, The mo lecular basis of the CNS effects of systemic inflammation are not full y elucidated, Here we show that the CNS responds to systemic inflammat ion with pronounced IL-1 beta gene expression and limited IL-1 recepto r antagonist (IL-1ra), IL-10, and IL-13 gene expression, This pattern occurs throughout the CNS, including areas such as the subfornical org an, pineal gland, neurohypophysis, and hypothalamus. In contrast, in t he anterior pituitary, we found limited IL-1 beta gene expression but marked induction of the mRNA encoding for the secreted isoform of IL-1 ra, secreted IL-1ra. We conclude that the central manifestations of pe ripheral inflammation are mediated by endogenous brain IL-1 beta synth esized during systemic inflammation in the context of limited central cytokine counter regulation of IL-1. As IL-1 beta is a potent stimulus for inducible nitric oxide synthase expression and activity, these fi ndings explain our previous observation that systemic inflammation pro motes inducible nitric oxide synthase gene expression in the brain and the spillover of NO metabolites into cerebrospinal fluid, The CNS tra nscription of the HIV-1 replication factor IL-1 beta in the context of limited transcription of the IL-1 replication inhibitors IL-1ra, IL-1 0, and IL-13 might help explain the negative impact of systemic inflam mation on the clinical course of AIDS. In addition, we propose that IL -1ra may be secreted by the anterior pituitary as a systemic anti-infl ammatory hormone that is released in response to IL-1 beta originated from multiple sources.