Molecular mechanisms of the central actions of interleukin-1

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It has been established that the central nervous system and the peripheral immune system interact in a biderectional manner. Interleukin-1 (IL-1) is one of the cytokines for the communication between these two systems. In this study, to clarify the cellular and molecular mechanisms for the central action of IL-1, we examined the effects of IL-1 on norepinephrine (NE) turnover (an index of noradrenergic neuronal activity) in the brain and peripheral organs in rats, and obtained the following results :1. When IL-1 was given intraperitoneally, it increased NE turnover in the hypothalamus and also in some peripheral organs such as spleen and lung. These responses were mimicked by an intracerebroventricular (icv) injection of minute amounts of IL-1, suggesting a direct action of IL-1 to the brain.2. The stimulative effects of IL-1 were completely blocked by the pretreatment with either an antibody against corticotropin-releasing hormone (CRH) or indomethacin, an inhibitor of prostaglandin (PG) biosynthesis, suggesting important roles of brain CRH and PGs for the IL-1 action.3. An icv injection of CRH could activate NE turnover in every organs in the same way as the IL-1 injection. In contrast, PGs given intracerebroventricularly were effective for NE turnover in some limited organs : that is , PGE2 for spleen and lung, and PGD2 only for the hypothalamus. Thus, the signal of IL-1 may be converted to the production of PGD2 and PGE2 to activate the noradrenergic neurons projecting to the hypothalamus and peripheral organs, respectively. The molecular mechanisms for such differential regulation of PG production in the brain remain to be further investigated.