Recombinant TNF-alpha mediated regulation of the I kappa B-alpha/NF-kappa B signaling pathway: evidence for the enhancement of pro- and anti-inflammatory cytokines in alveolar epithelial cells.
The signaling transduction mechanism mediated by tumor necrosis factor-alpha (TNF-alpha) in the alveolar epithelium is not well characterized. It was subsequently hypothesized that recombinant murine TNF-alpha (rmTNF-alpha) selectively regulates the inhibitory kappa B (I kappa B-alpha)/nuclear factor-kappa B (NF-kappa B) pathway and interferes with the endogenous biosynthesis of pro-inflammatory (stimulatory) and anti-inflammatory (inhibitory) cytokines. The cytokine rmTNF-alpha induced, in a time- and dose-dependent manner, the degradation of I kappa B-alpha within the cytosolic compartment, an effect associated with up-regulating its phosphorylation. This allowed the biphasic regulation of selective NF-kappa B subunit nuclear translocation, thereby mediating a dual excitatory mechanism on NF-kappa B activation. The immunoregulatory effect of rmTNF-alpha was associated with a time-dependent induction of pro-inflammatory [interleukin (IL)-1 beta, IL-6 and TNF-alpha] and anti-inflammatory (IL-10) cytokine biosynthesis. These results indicate a novel involvement of an I kappa B-alpha/NF-kappa B-sensitive pathway mediating the effect of TNF-alpha, which is associated with an autocrine, endogenous mechanism mediating the regulation of cytokine signaling.
Haddad
John J
JJ
Neuroscience Research Laboratory, Department of Anesthesia & Perioperative Care, University of California, Medical Center S-261, San Francisco, California 94143-0542, USA. haddadj@anesthesia.ucsf.edu
D000818:Animals; D016207:Cytokines / Q000502:physiology*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D020672:I-kappa B Proteins / Q000187:drug effects / Q000502:physiology*; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000187:drug effects / Q000502:physiology*; D011247:Pregnancy; D011650:Pulmonary Alveoli / Q000187:drug effects / Q000196:embryology / Q000276:immunology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000494:pharmacology; D020545:Respiratory Mucosa / Q000187:drug effects / Q000276:immunology*; D015398:Signal Transduction / Q000187:drug effects*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D016207:Cytokines; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606206:Nfkbia protein, rat; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D000072000:NF-KappaB Inhibitor alpha