Involvement of Corticotropin-Releasing Hormone- And Interleukin (IL)-6-dependent Proopiomelanocortin Induction in the Anterior Pituitary During Hypothalamic-Pituitary-Adrenal Axis Activation by IL-1alpha

Endocrinology. 2005 Dec;146(12):5496-502. doi: 10.1210/en.2005-0409. Epub 2005 Sep 1.

Abstract

IL-1alpha/beta 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-1alpha induced a normal HPAA activation in IL-1alpha/beta 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-1alpha/beta 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-1alpha was reduced in IL-1alpha/beta KO and IL-6 KO mice, as well as in CRH KO mice, suggesting IL-1alpha/beta, 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-1alpha, were reduced in IL-1alpha/beta KO mice. Because IL-1alpha-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-1alpha, 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-1alpha/beta in the induction of POMC in the AP through the induction of two independent pathways, CRH and IL-6.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Corticotropin-Releasing Hormone / metabolism*
  • Hypothalamo-Hypophyseal System / drug effects*
  • Interleukin-1 / deficiency
  • Interleukin-1 / pharmacology*
  • Interleukin-6 / deficiency
  • Interleukin-6 / metabolism*
  • Mice
  • Mice, Knockout
  • Paraventricular Hypothalamic Nucleus / drug effects
  • Paraventricular Hypothalamic Nucleus / metabolism
  • Pituitary Gland, Anterior / metabolism*
  • Pituitary-Adrenal System / drug effects*
  • Pro-Opiomelanocortin / biosynthesis*
  • Recombinant Proteins / pharmacology
  • STAT3 Transcription Factor / physiology

Substances

  • Interleukin-1
  • Interleukin-6
  • Recombinant Proteins
  • STAT3 Transcription Factor
  • Pro-Opiomelanocortin
  • Corticotropin-Releasing Hormone