Protective effect of ciliary neurotrophic factor (CNTF) in a model of endotoxic shock: action mechanisms and role of CNTF receptor alpha.
Ciliary neurotrophic factor (CNTF) inhibits the production of tumor necrosis factor (TNF) in lipopolysaccharide (LPS)-treated mice and protects against LPS lethality when coadministered with its soluble receptor (sCNTFR alpha). Both of these activities are abolished in adrenalectomized (ADX) mice. LPS-induced pulmonary polymorphonuclear neutrophil (PMN) infiltration and nitric oxide (NO) production were also inhibited 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 toxicity in a manner related to their affinity for the beta components of CNTFR. Thus, inhibition of TNF production and protection against LPS lethality by CNTF/sCNTFR alpha require an intact hypothalamus-pituitary-adrenal axis (HPAA) and may be mediated by endogenous glucocorticoids. This protective effect is, at least in part, due to the inhibition of PMN infiltration and NO production, and appears to be mediated by cells displaying only beta-receptor subtypes.
Demitri
M T
MT
Mario Negri Institute for Pharmacological Research, Milan, Italy.
Benigni
F
F
Meazza
C
C
Zinetti
M
M
Fratelli
M
M
Villa
P
P
Acheson
A
A
Panayotatos
N
N
Ghezzi
P
P
D000315:Adrenalectomy; D000818:Animals; D020934:Ciliary Neurotrophic Factor; D004195:Disease Models, Animal; D006801:Humans; D008070:Lipopolysaccharides / Q000633:toxicity; D008168:Lung / Q000201:enzymology; D008297:Male; D008657:Metabolic Clearance Rate; D051379:Mice; D008807:Mice, Inbred BALB C; D009419:Nerve Tissue Proteins / Q000493:pharmacokinetics / Q000627:therapeutic use*; D018696:Neuroprotective Agents; D009566:Nitrates / Q000097:blood; D009573:Nitrites / Q000097:blood; D009195:Peroxidase / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000502:physiology*; D020801:Receptor, Ciliary Neurotrophic Factor; D017475:Receptors, Nerve Growth Factor / Q000502:physiology*; D011994:Recombinant Proteins; D012772:Shock, Septic / Q000517:prevention & control*; D014018:Tissue Distribution; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D020934:Ciliary Neurotrophic Factor; D008070:Lipopolysaccharides; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D009566:Nitrates; D009573:Nitrites; D020801:Receptor, Ciliary Neurotrophic Factor; D017475:Receptors, Nerve Growth Factor; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D009195:Peroxidase; D020794:Receptor Protein-Tyrosine Kinases