title: Biphasic activation of p38MAPK suggests that apoptosis is a downstream event in pemphigus acantholysis.
abstract: In pemphigus vulgaris and pemphigus foliaceus (PF), autoantibodies against desmoglein-3 and desmoglein-1 induce epidermal cell detachment (acantholysis) and blistering. Activation of keratinocyte intracellular signaling pathways is emerging as an important component of pemphigus IgG-mediated acantholysis. We previously reported activation of p38 mitogen-activated protein kinase (MAPK) in response to pathogenic pemphigus vulgaris and PF IgG. Inhibition of p38MAPK blocked pemphigus IgG-induced cytoskeletal reorganization in tissue culture and blistering in pemphigus mouse models. We now extend these observations by demonstrating two peaks of p38MAPK activation in pemphigus tissue culture and mouse models. Administration of the p38MAPK inhibitor SB202190 before PF IgG injection blocked both peaks of p38MAPK phosphorylation and blister formation, consistent with our previous findings; however, administration of the inhibitor 4 h after PF IgG injection blocked only the later peak of p38MAPK activation but failed to block blistering. Examination of the temporal relationship of p38MAPK phosphorylation and apoptosis showed that apoptosis occurs at or after the second peak of p38MAPK activation. The time course of p38MAPK activation and apoptotic markers, as well as the ability of inhibitors of p38MAPK to block activation of the proapoptotic proteinase caspase-3, suggest that activation of apoptosis is downstream to, and a consequence of, p38MAPK activation in pemphigus acantholysis. Furthermore, these observations suggest that the earlier peak of p38MAPK activation is part of the mechanism leading to acantholysis, whereas the later peak of p38MAPK and apoptosis may not be essential for acantholysis.
authors.affiliation: Department of Dermatology, The University of North Carolina School of Medicine, Chapel Hill, NC 27599-7287, USA.
authors.forename: Hua En
authors.initials: HE
authors.lastname: Lee
authors.forename: Paula
authors.initials: P
authors.lastname: Berkowitz
authors.forename: Puneet S
authors.initials: PS
authors.lastname: Jolly
authors.forename: Luis A
authors.initials: LA
authors.lastname: Diaz
authors.forename: Michael P
authors.initials: MP
authors.lastname: Chua
authors.forename: David S
authors.initials: DS
authors.lastname: Rubenstein
mesh_terms: D000051:Acantholysis / Q000201:enzymology* / Q000473:pathology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001323:Autoantibodies / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D003599:Cytoskeleton / Q000378:metabolism / Q000473:pathology; D051183:Desmoglein 1 / Q000378:metabolism; D051184:Desmoglein 3 / Q000378:metabolism; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D007074:Immunoglobulin G / Q000378:metabolism; D051379:Mice; D010392:Pemphigus / Q000201:enzymology* / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D046509:Tissue Culture Techniques; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D001323:Autoantibodies; C071894:DSG3 protein, human; D051183:Desmoglein 1; D051184:Desmoglein 3; C495300:Dsg3 protein, mouse; D007074:Immunoglobulin G; D047428:Protein Kinase Inhibitors; D048051:p38 Mitogen-Activated Protein Kinases; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; D053148:Caspase 3