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Hypothalamic Interleukin-1ß and Tumor Necrosis Factor-, But Not Interleukin-6, Mediate the Endotoxin-Induced Suppression of the Reproductive Axis in Rats

Clinical Research Center (H.W.) and Rehabilitation Center (Y.H.), International University of Health and Welfare, Otawara, Tochigi 324-8501, Japan

Address all correspondence and requests for reprints to: Hajime Watanobe, M.D., Division of Internal Medicine, Clinical Research Center, International University of Health and Welfare, 2600-1 Kitakanemaru, Otawara, Tochigi 324-8501, Japan. E-mail: watah{at}iuhw.ac.jp.

It is well established that endotoxemia disrupts reproductive capability, and several proinflammatory cytokines, especially IL-1ß, IL-6, and TNF- in the brain, have been implicated in this endocrine aberration. However, no previous study has directly compared the effects of the three major proinflammatory cytokines (IL-1ß, IL-6, and TNF-) on the in vivo release of hypothalamic GnRH, a secretagogue of LH from the pituitary. Therefore, in this study, we addressed this issue with two complementary approaches involving push-pull perfusion in freely moving ovariectomized female rats. First, we examined the effects of systemic lipopolysaccharide (LPS) treatment on the release of plasma LH, and of GnRH, IL-1ß, IL-6, and TNF- in the hypothalamic medial preoptic area (MPOA), where the majority of GnRH neuronal perikarya are located. LPS inhibited the secretion of both LH and GnRH and concomitantly stimulated the release of all three cytokines. We next tested the effects of direct MPOA perfusion with the respective cytokines (at three different concentrations each) on the GnRH and LH secretion. IL-1ß and TNF-, at the concentrations that were observed in the MPOA after the LPS injection, were equipotent in inhibiting the GnRH-LH system, whereas IL-6 was ineffective (even at a supraphysiological concentration). These results strongly suggest that IL-1ß and TNF- may represent the major proinflammatory cytokines mediating the LPS-induced suppression of GnRH and LH release, whereas the role of IL-6 seems to be insignificant.

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