Molecular mechanisms of apoptosis induced by an immunomodulating peptide on human monocytes.
A short immunomodulating peptide (Pa) containing a defined structural motif present in a number of extracellular matrix proteins and autoantigens was found to stimulate human monocytes. Pa-induced apoptosis of isolated monocytes, as indicated by internucleosomal DNA cleavage, increased annexin V binding capacity and cleavage of caspase substrates, such as poly(ADP)ribosylpolymerase. In addition, Bcl-2 protein levels were downregulated during Pa-induced cell death. Nuclear extracts of monocytes incubated with Pa showed higher neutral, Ca(2+)-dependent DNase activity than those obtained from nontreated monocytes. Caspase inhibitors prevented Pa-induced apoptosis, Bcl-2 depletion, and DNase activation. Treatment of monocytes with Pa activated c-Jun N-terminal kinases and p38 kinase, in an acidic sphingomyelinase- and caspase-dependent fashion. Pa-induced apoptosis was blocked by selective inhibitors of p38 kinase (SB203580) and acidic sphingomyelinase (SR33557). These results indicate that JNK and p38 kinase stimulation as well as monocyte apoptosis induced by Pa could depend, at least in part, on early activation of acidic sphingomyelinase.
Osés-Prieto
J A
JA
Department of Biochemistry, University of Navarra, Pamplona, Spain.
López-Moratalla
N
N
Santiago
E
E
Jaffrézou
J P
JP
López-Zabalza
M J
MJ
D000276:Adjuvants, Immunologic / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000494:pharmacology*; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D017304:Annexin A5 / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects*; D001324:Autoantigens / Q000737:chemistry / Q000276:immunology; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D002467:Cell Nucleus / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D002478:Cells, Cultured; D053938:DNA Fragmentation / Q000187:drug effects; D003851:Deoxyribonucleases / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016326:Extracellular Matrix Proteins / Q000737:chemistry / Q000276:immunology; D020730:Guanine Nucleotide Dissociation Inhibitors / Q000378:metabolism; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D008969:Molecular Sequence Data; D009000:Monocytes / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology; D010455:Peptides / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000276:immunology / Q000494:pharmacology*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D013108:Sphingomyelin Phosphodiesterase / Q000037:antagonists & inhibitors / Q000378:metabolism; D062947:rho-Specific Guanine Nucleotide Dissociation Inhibitors
D000276:Adjuvants, Immunologic; D017304:Annexin A5; D001324:Autoantigens; D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D016326:Extracellular Matrix Proteins; D020730:Guanine Nucleotide Dissociation Inhibitors; D010455:Peptides; D019253:Proto-Oncogene Proteins c-bcl-2; D062947:rho-Specific Guanine Nucleotide Dissociation Inhibitors; D011065:Poly(ADP-ribose) Polymerases; D020928:Mitogen-Activated Protein Kinases; D003851:Deoxyribonucleases; D013108:Sphingomyelin Phosphodiesterase; D020169:Caspases