Vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide inhibit tumor necrosis factor alpha transcriptional activation by regulating nuclear factor-kB and cAMP response element-binding protein/c-Jun.
Tumor necrosis factor alpha (TNFalpha), an early cytokine produced by activated macrophages, plays an essential role in normal and pathological inflammatory reactions. The excessive production of TNFalpha is prevented by the so-called "macrophage-deactivating factors." This study examines the role of two structurally related neuropeptides, the vasoactive intestinal peptide (VIP) and the pituitary adenylate cyclase-activating peptide (PACAP), as inhibitors of TNFalpha. Both VIP and PACAP inhibit TNFalpha production from lipopolysaccharide-stimulated RAW 246.7 cells in a dose- and time-dependent manner. Although the activated cells express mRNA for all three VIP/PACAP receptors, agonist and antagonist studies indicate that the major receptor involved is VIP1R. VIP/PACAP inhibit TNFalpha gene expression by affecting both NF-kB binding and the composition of the cAMP responsive element binding complex (CREB/c-Jun). Two transduction pathways, a cAMP-dependent and a cAMP-independent pathway, are involved in the inhibition of TNFalpha gene expression and appear to differentially regulate the transcriptional factors involved. Because TNFalpha plays a central role in various inflammatory diseases such as endotoxic shock, multiple sclerosis, cerebral malaria, and various autoimmune conditions, the down-regulatory effect of VIP/PACAP may have a significant therapeutic potential.
Delgado
M
M
Department of Biological Sciences, Rutgers University, Newark, New Jersey 07102, USA.
Munoz-Elias
E J
EJ
Kan
Y
Y
Gozes
I
I
Fridkin
M
M
Brenneman
D E
DE
Gomariz
R P
RP
Ganea
D
D
D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D002460:Cell Line; D000242:Cyclic AMP / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D005786:Gene Expression Regulation; D048031:JNK Mitogen-Activated Protein Kinases; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D051379:Mice; D020928:Mitogen-Activated Protein Kinases; D016328:NF-kappa B / Q000378:metabolism; D009479:Neuropeptides / Q000494:pharmacology*; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D011485:Protein Binding; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D051236:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide; D011979:Receptors, Pituitary Hormone / Q000378:metabolism; D018005:Receptors, Vasoactive Intestinal Peptide / Q000378:metabolism; D020218:Response Elements; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*; D014660:Vasoactive Intestinal Peptide / Q000494:pharmacology*
C495402:Adcyap1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D008070:Lipopolysaccharides; D016328:NF-kappa B; D009479:Neuropeptides; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D016755:Proto-Oncogene Proteins c-jun; D051236:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide; D011979:Receptors, Pituitary Hormone; D018005:Receptors, Vasoactive Intestinal Peptide; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D014660:Vasoactive Intestinal Peptide; D000242:Cyclic AMP; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases