PROTECTIVE EFFECT OF CILIARY NEUROTROPHIC FACTOR (CNTF) IN A MODEL OFENDOTOXIC-SHOCK - ACTION MECHANISMS AND ROLE OF CNTF RECEPTOR-ALPHA

Ciliary neurotrophic factor (CNTF) inhibits the production of tumor ne crosis factor (TNF) in lipopolysaccharide (LPS)-treated mice and prote cts against LPS lethality when coadministered with its soluble recepto r (sCNTFR alpha). Both of these activities are abolished in adrenalect omized (ADX) mice. LPS-induced pulmonary polymorphonuclear neutrophil (PMN) infiltration and nitric oxide (NO) production were also inhibite d by CNTF + sCNTFR alpha but not by CNTF alone. sCNTFR alpha: did not alter the clearance or tissue distribution of CNTF. Furthermore, CNTF variants coadministered with sCNTFR alpha protected against LPS toxici ty in a manner related to their affinity for the beta components of CN TFR. Thus inhibition Of TNF production and protection against LPS leth ality by CNTF/sCNTFR alpha require an intact hypothalamus-pituitary-ad renal axis (HPAA) and may be mediated by endogenous glucocorticoids. T his protective effect is, at least in part, due to the inhibition of P MN infiltration and NO production, and appears to be mediated by cells displaying only beta-receptor subtypes. (C) 1998 Wiley-Liss, Inc.