A potent immunosuppressive retroviral peptide: cytokine patterns and signaling pathways.
A synthetic bioactive peptide composed of 17 amino acids (CKS-17) homologous to a highly conserved region of human and animal retroviral transmembrane envelope proteins induces not only significant immunoregulatory functions but also exhibits Th1-inhibiting properties, as described by its ability to suppress cell-mediated immunity and inhibit the production of interleukin (IL) 12, IL-2, gamma interferon, and tumor necrosis factor alpha, while enhancing IL-10. An important molecular mechanism responsible for the observed cytokine profiles by CKS-17 is provided by our findings demonstrating that this small peptide activates several intracellular signaling molecules, i.e., elevates intracellular cyclic adenosine monophosphate (cAMP) levels, and induces phosphorylation of extracellular signal-regulated kinase (ERK) 1 and 2, mitogen-activated protein kinase/ERK kinase (MEK), protein kinase D, Raf1, and phospholipase C gamma1 (PLCgamma1). The activation of ERK1/2 is via the PLCgamma1-protein kinase C-Raf1-MEK signaling cascade. The activation of both ERK1/2 and cAMP appears to be via a mechanism sensitive to AG879, a receptor tyrosine kinase inhibitor, but not to AG825, AG1296, or AG1478. Furthermore, phosphoinositide-3 kinase appears to mediate the CKS-17-induced activation of ERK1/2, but not of cAMP. A specific amino acid sequence as well as the dimerization of this peptide is required to confer these biological activities. The results obtained are compelling and reproducible. This highly conserved molecule may enable us to understand a basic mechanism(s) of intracellular signaling pathways, regulation of Th1/Th2 cytokines, immunosuppression, and immunologic tolerance.
Haraguchi
Soichi
S
Division of Allergy, Immunology, and Rheumatology, Department of Pediatrics, University of South Florida, Children's Research Institute, 140 Seventh Avenue South, CRI 4008, St. Petersburg, FL 33701, USA. sharaguc@health.usf.edu
Good
Robert A
RA
Day-Good
Noorbibi K
NK
D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D016207:Cytokines / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007108:Immune Tolerance; D007165:Immunosuppression Therapy; D036341:Intercellular Signaling Peptides and Proteins; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008969:Molecular Sequence Data; D010455:Peptides / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology; D012190:Retroviridae; D015682:Retroviridae Proteins, Oncogenic / Q000235:genetics; D015290:Second Messenger Systems / Q000187:drug effects / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology*; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology*; D018418:Th2 Cells / Q000187:drug effects / Q000276:immunology*; D014759:Viral Envelope Proteins / Q000235:genetics
D016207:Cytokines; D004791:Enzyme Inhibitors; D036341:Intercellular Signaling Peptides and Proteins; D010455:Peptides; D015682:Retroviridae Proteins, Oncogenic; D014759:Viral Envelope Proteins; C078678:p15E protein, Murine leukemia virus; C053692:CKS 17