Vasoactive intestinal peptide and pituitary adenylate cyclase activating polypeptide inhibit the MEKK1/MEK4/JNK signaling pathway in LPS-stimulated macrophages.
The vasoactive intestinal peptide (VIP) and the pituitary adenylate cyclase activating polypeptide (PACAP), two immunomodulatory neuropeptides that affect both innate and acquired immunity, downregulate TNFalpha expression in LPS-stimulated peritoneal macrophages and Raw 264.7 cells. We showed previously that VIP/PACAP change the composition of the CRE-binding complex in the TNFalpha promoter from highc-Jun/(low)CREB, characteristic for LPS-stimulated macrophages, to lowc-Jun/(high)CREB, characteristic for the unstimulated cells. In the present study we examined the effects of VIP/PACAP on the MEKK1/MEK4/JNK transduction pathway, and on the subsequent changes in Jun family members. Our studies indicate that VIP/PACAP inhibit MEKK1 activity, and the subsequent phosphorylation of MEK4, JNK, and c-Jun. Treatment with VIP or PACAP results in a decrease in AP-1 binding, and a marked change in the composition of the AP-1 complexes from c-Jun/c-Fos to JunB/c-Fos. Western blots confirm that VIP stimulates JunB production in LPS-stimulated macrophages. Both the inhibition of the MEKK1/MEK4/JNK pathway, leading to the reduction in phosphorylated c-Jun, and the stimulation of JunB, are mediated through the specific VPAC1 receptor and the cAMP/PKA pathway. The VIP/PACAP interference with the stress-induced SAPK/JNK pathway in stimulated macrophages may represent a significant element in the regulation of the inflammatory response by the endogenous neuropeptides.
Delgado
M
M
Department of Biological Sciences, Rutgers University, 101 Warren St., Newark, NJ 07102, USA.
Ganea
D
D
D000818:Animals; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases; D008070:Lipopolysaccharides / Q000494:pharmacology; D048670:MAP Kinase Kinase 4; D048728:MAP Kinase Kinase Kinase 1; D048768:MAP Kinase Kinase Kinase 4; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000276:immunology; D008264:Macrophages / Q000166:cytology / Q000201:enzymology* / Q000276:immunology; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism*; D015213:Neuroimmunomodulation / Q000276:immunology; D009479:Neuropeptides / Q000494:pharmacology*; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D011485:Protein Binding / Q000187:drug effects / Q000276:immunology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D018005:Receptors, Vasoactive Intestinal Peptide / Q000378:metabolism; D051238:Receptors, Vasoactive Intestinal Polypeptide, Type I; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014660:Vasoactive Intestinal Peptide / Q000494:pharmacology*
C495402:Adcyap1 protein, mouse; D008070:Lipopolysaccharides; D009479:Neuropeptides; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D016755:Proto-Oncogene Proteins c-jun; D018005:Receptors, Vasoactive Intestinal Peptide; D051238:Receptors, Vasoactive Intestinal Polypeptide, Type I; D018808:Transcription Factor AP-1; D014660:Vasoactive Intestinal Peptide; D000242:Cyclic AMP; D017346:Protein Serine-Threonine Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048728:MAP Kinase Kinase Kinase 1; D048768:MAP Kinase Kinase Kinase 4; D020930:MAP Kinase Kinase Kinases; C482578:Map3k1 protein, mouse; C482780:Map3k4 protein, mouse; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases