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Involvement of Corticotropin-Releasing Hormone- and Interleukin (IL)-6-Dependent Proopiomelanocortin Induction in the Anterior Pituitary during Hypothalamic-Pituitary-Adrenal Axis Activation by IL-1

Division of Cell Biology (D.C., Y.I.), Center for Experimental Medicine, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo 108-8639, Japan; Department of Bioregulation (T.I.), Institute of Development and Aging Sciences, Nippon Medical School, Kanagawa 211-8533, Japan; and Third Department of Internal Medicine (T.S.), Hirosaki University School of Medicine, Hirosaki 036-8562, Japan

Address all correspondence and requests for reprints to: Yoichiro Iwakura, D. Sc., Center for Experimental Medicine, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan. E-mail: iwakura{at}ims.u-tokyo.ac.jp.

IL-1/ß and IL-6 are endogenous modulator of hypothalamo-pituitary-adrenal axis (HPAA) and are thought to play key roles in immune-neuroendocrine interactions during inflammation. Here, we show IL-1 induced a normal HPAA activation in IL-1/ß knockout (KO) and IL-6 KO mice at 1 h; however, at 6 h HPAA activation was reduced relative to wild-type mice, indicating a role for endogenous IL-1/ß and IL-6 in prolonged HPAA activation. We found that the induction of proopiomelanocortin (POMC) transcript in the anterior pituitary (AP) at 6 h in response to IL-1 was reduced in IL-1/ß KO and IL-6 KO mice, as well as in CRH KO mice, suggesting IL-1/ß, IL-6, and CRH are all required for POMC induction. The induction of CRH transcript in the paraventricular nucleus at 6 h and plasma IL-6 levels, in response to IL-1, were reduced in IL-1/ß KO mice. Because IL-1-induced activation of signal transducer and activator of transcription 3 in the AP was also suppressed in IL-6 KO mice, we suggest that plasma IL-6 is first induced by IL-1, and IL-6 activates signal transducer and activator of transcription 3 in the AP, leading to the induction of POMC in concert with CRH. Our results suggest a role for IL-1/ß in the induction of POMC in the AP through the induction of two independent pathways, CRH and IL-6.

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