Recombinant tumor necrosis factor-alpha potentiates neutrophil degranulation in response to host defense cytokines neutrophil-activating peptide 2 and IL-8 by modulating intracellular cyclic AMP levels.
The neutrophil-activating peptide 2 (NAP-2) and IL-8 are closely related in structure and function. In order to further determine their potential biologic roles in inflammation, we studied their interaction with TNF-alpha-primed human polymorphonuclear neutrophil granulocytes at the levels of effector functions and signal transduction. After short term priming (5 min) by TNF-alpha, suspended cytochalasin B-treated PMN responded to NAP-2 or rIL-8 by substantial augmentation of the degranulation response. After priming with 3 ng/ml TNF-alpha marker release from both azurophilic and specific granules was near maximum. NAP-2 and rIL-8 cooperated with TNF-alpha in very similar ways, as indicated by the almost identical increases in release rates that were induced by equipotent doses of either secondary stimulus. At the signal transduction level, pharmacologic elevation of intracellular cAMP led to the inhibition of NAP-2- or rIL-8-induced degranulation in primed and unprimed PMN, indicating a role for this second messenger as a negative feedback signal. Direct measurement of intracellular cAMP revealed that TNF-alpha by itself did not affect its levels. Instead, TNF-alpha reduced both the scale as well as the duration of the cAMP burst generated in response to secondary stimuli NAP-2 or rIL-8. Thus, there is evidence that TNF-alpha priming of neutrophils for enhanced NAP-2- or rIL-8-promoted degranulation involves the antagonistic down-modulation of stimulus-induced rises in cAMP.
Brandt
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Forschungsinstitut Borstel, Department of Immunology and Cell Biology, Germany.
Petersen
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F
Flad
H D
HD
D015550:Cell Degranulation / Q000187:drug effects*; D000242:Cyclic AMP / Q000378:metabolism*; D006152:Cyclic GMP / Q000378:metabolism; D003571:Cytochalasin B / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D006801:Humans; D066298:In Vitro Techniques; D016209:Interleukin-8 / Q000008:administration & dosage*; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology*; D010455:Peptides / Q000008:administration & dosage*; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage*; D001620:beta-Thromboglobulin
D016209:Interleukin-8; C061615:PPBP protein, human; D010455:Peptides; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D001620:beta-Thromboglobulin; D003571:Cytochalasin B; C009862:connective tissue-activating peptide; D000242:Cyclic AMP; D006152:Cyclic GMP