INTERLEUKIN-1-BETA (IL-1-BETA)-INDUCED MODULATION OF THE HYPOTHALAMICIL-1-BETA SYSTEM, TUMOR-NECROSIS-FACTOR-ALPHA, AND TRANSFORMING GROWTH-FACTOR-BETA-1 MESSENGER-RNAS IN OBESE (FA FA) AND LEAN (FA/FA) ZUCKER RATS - IMPLICATIONS TO IL-1-BETA FEEDBACK-SYSTEMS AND CYTOKINE-CYTOKINE INTERACTIONS/

Interleukin-1 beta (IL-1 beta) induces anorexia, fever, sleep changes, and neuroendocrine alterations when administered into the brain. Here , we investigated the regulation of the IL-1 beta system (ligand, rece ptors, receptor accessory protein, and receptor antagonist), tumor nec rosis factor-alpha (TNF-alpha), transforming growth factor (TGF)-beta 1, and TGF-alpha mRNAs in the hypothalamus of obese (fa/fa) and lean ( Fa/Fa) Zucker rats in response to the intracerebroventricular microinf usion of IL-1 beta (8.0 ng/24 hr for 72 hr, a dose that yields estimat ed pathophysiological concentrations in the cerebrospinal fluid). IL-1 beta increased IL-1 beta, IL-1 receptor types I and II (IL-1RI and IL -1RII), IL-1 receptor accessory protein soluble form (IL-1R AcP II), I L-1 receptor antagonist (IL-1Ra), TNF-a, and TGF-beta 1 mRNAs in the h ypothalamus from obese and lean rats. IL-1 beta-induced IL-1 beta syst em and ligand (IL-1 beta, TNF-alpha, and TGF-beta 1) mRNA profiles wer e highly intercorrelated in the same samples. Levels of membrane-bound IL-1R AcP and TGF-alpha mRNAs did not change. Heat-inactivated IL-1 b eta had no effect. The data suggest 1) the operation of an IL-1 beta f eedback system (IL-1 beta/IL-1RI/IL-1R Acp II/IL-1RII/IL-1Ra) and 2) p otential cytokine-cytokine interactions with positive (IL-1 beta <---- > TNF-alpha) and negative (TGF-beta-->IL-1 beta/TNF-alpha) feedback. D ysregulation of the IL-1 beta feedback system and the TGF-beta 1/IL-1 beta-TNF-alpha balance may have implications for neurological disorder s associated with high levels of IL-1 beta in the brain. (C) 1997 Wile y-Liss, Inc.