Human Langerhans-cell activation triggered in vitro by conditionally expressed MKK6 is counterregulated by the downstream effector RelB.
Environmentally exposed epithelial Langerhans cells (LCs) encounter diverse innate stress signals, which lead to the activation of complex intracellular signaling cascades. Among these, p38 MAPK is consistently phosphorylated. For which aspects of LC activation triggering of p38 signaling is sufficient remains to be elucidated. We show that conditional induction of a dominant active form of MAPK kinase 6 (d.a.MKK6), a direct upstream kinase of p38, in LCs efficiently induces the up-regulation of costimulatory molecules and enhances their T-cell stimulatory capacity. These immediate effects showed no or only a minor requirement for classical NF-kappaB signaling. Concomitant with LC activation, d.a.MKK6 induced the alternative NF-kappaB member RelB, whose nuclear localization marks mature DCs. Specific inhibition of nuclear RelB during d.a.MKK6-induced LC activation further enhanced their maturation state. This observation was validated using the p38 activator anisomycin, thus suggesting a novel LC intrinsic control mechanism regulated by RelB.
Jörgl
Almut
A
Institute of Immunology, Medical University Vienna, Austria.
Platzer
Barbara
B
Taschner
Sabine
S
Heinz
Leonhard X
LX
Höcher
Bernhard
B
Reisner
Peter M
PM
Göbel
Florian
F
Strobl
Herbert
H
D000841:Anisomycin / Q000494:pharmacology; D017951:Antigen Presentation; D018122:B7-1 Antigen / Q000096:biosynthesis / Q000235:genetics; D051940:B7-2 Antigen / Q000096:biosynthesis / Q000235:genetics; D020170:Caspase 1 / Q000378:metabolism; D002454:Cell Differentiation; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured / Q000166:cytology / Q000378:metabolism; D016895:Culture Media, Serum-Free; D016207:Cytokines / Q000494:pharmacology; D004318:Doxycycline / Q000494:pharmacology; D004789:Enzyme Activation; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D005799:Genes, Dominant; D006801:Humans; D053583:Interleukin-1beta / Q000096:biosynthesis / Q000235:genetics; D007801:Langerhans Cells / Q000166:cytology* / Q000378:metabolism; D048669:MAP Kinase Kinase 6 / Q000235:genetics / Q000502:physiology*; D018448:Models, Immunological; D016328:NF-kappa B / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000187:drug effects; D017475:Receptors, Nerve Growth Factor / Q000096:biosynthesis / Q000235:genetics; D013601:T-Lymphocytes / Q000276:immunology; D051841:Transcription Factor RelB / Q000502:physiology*; D020298:U937 Cells; D015854:Up-Regulation; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D018122:B7-1 Antigen; D051940:B7-2 Antigen; D016895:Culture Media, Serum-Free; D016207:Cytokines; D053583:Interleukin-1beta; D016328:NF-kappa B; C484065:NGFR protein, human; D009419:Nerve Tissue Proteins; C497593:RELB protein, human; D017475:Receptors, Nerve Growth Factor; D051841:Transcription Factor RelB; D000841:Anisomycin; D048051:p38 Mitogen-Activated Protein Kinases; D048669:MAP Kinase Kinase 6; C482566:MAP2K6 protein, human; D020170:Caspase 1; D004318:Doxycycline