Ciliary neurotrophic factor inhibits brain and peripheral tumor necrosis factor production and, when coadministered with its soluble receptor, protects mice from lipopolysaccharide toxicity.
BACKGROUND
The receptor of ciliary neurotrophic factor (CNTF) contains the signal transduction protein gp130, which is also a component of the receptors of cytokines such as interleukin (IL)-6, leukemia-inhibitory factor (LIF), IL-11, and oncostatin M. This suggests that these cytokines might share common signaling pathways. We previously reported that CNTF augments the levels of corticosterone (CS) and of IL-6 induced by IL-1 and induces the production of the acute-phase protein serum amyloid A (SAA). Since the elevation of serum CS is an important feedback mechanism to limit the synthesis of proinflammatory cytokines, particularly tumor necrosis factor (TNF), we have investigated the effect of CNTF on both TNF production and lipopolysaccharide (LPS) toxicity.


METHODS
To induce serum TNF levels, LPS was administered to mice at 30 mg/kg i.p. and CNTF was administered as a single dose of 10 micrograms/mouse i.v., either alone or in combination with its soluble receptor sCNTFR alpha at 20 micrograms/mouse. Serum TNF levels were the measured by cytotoxicity on L929 cells. In order to measure the effects of CNTF on LPS-induced TNF production in the brain, mice were injected intracerebroventricularly (i.c.v.) with 2.5 micrograms/kg LPS. Mouse spleen cells cultured for 4 hr with 1 microgram LPS/ml, with or without 10 micrograms CNTF/ml, were also analyzed for TNF production.


RESULTS
CNTF, administered either alone or in combination with its soluble receptor, inhibited the induction of serum TNF levels by LPS. This inhibition was also observed in the brain when CNTF and LPS were administered centrally. In vitro, CNTF only marginally affected TNF production by LPS-stimulated mouse splenocytes, but it acted synergistically with dexamethasone (DEX) in inhibiting TNF production. Most importantly, CNTF administered together with sCNTFR alpha protected mice against LPS-induced mortality.


CONCLUSIONS
These data suggest that CNTF might act as a protective cytokine against TNF-mediated pathologies both in the brain and in the periphery.
Mario Negri Institute for Pharmacological Research, Milan, Italy.
F
F
Benigni
P
P
Villa
M T
MT
Demitri
S
S
Sacco
J D
JD
Sipe
L
L
Lagunowich
N
N
Panayotatos
P
P
Ghezzi
D000818:Animals; D001921:Brain / Q000378:metabolism*; D002478:Cells, Cultured; D020934:Ciliary Neurotrophic Factor; D003345:Corticosterone / Q000097:blood; D003907:Dexamethasone / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000633:toxicity*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009414:Nerve Growth Factors / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D009419:Nerve Tissue Proteins / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D020801:Receptor, Ciliary Neurotrophic Factor; D017475:Receptors, Nerve Growth Factor / Q000378:metabolism*; D000685:Serum Amyloid A Protein / Q000378:metabolism; D013154:Spleen / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
D020934:Ciliary Neurotrophic Factor; D008070:Lipopolysaccharides; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D020801:Receptor, Ciliary Neurotrophic Factor; D017475:Receptors, Nerve Growth Factor; D000685:Serum Amyloid A Protein; D014409:Tumor Necrosis Factor-alpha; D003907:Dexamethasone; D003345:Corticosterone