title: Cell type-specific targeting dissociates the therapeutic from the adverse effects of protein kinase inhibition in allergic skin disease.
abstract: The kinase p38α, originally identified because of its endotoxin- and cytokine-inducible activity and affinity for antiinflammatory compounds, has been posited as a promising therapeutic target for various immune-mediated disorders. In clinical trials, however, p38α inhibitors produced adverse skin reactions and other toxic effects that often outweighed their benefits. Such toxicity may arise from a perturbation of physiological functions unrelated to or even protective against the disease being treated. Here, we show that the effect of interfering with p38α signaling can be therapeutic or adverse depending on the targeted cell type. Using a panel of mutant mice devoid of p38α in distinct cell types and an experimental model of allergic skin disease, we find that dendritic cell (DC)-intrinsic p38α function is crucial for both antigen-specific T-cell priming and T-cell-mediated skin inflammation, two independent processes essential for the immunopathogenesis. By contrast, p38α in other cell types serves to prevent excessive inflammation or maintain naïve T-cell pools in the peripheral lymphoid tissues. These findings highlight a dilemma in the clinical use of p38α inhibitors, yet also suggest cell-selective targeting as a potential solution for improving their therapeutic index.
authors.affiliation: Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA.
authors.forename: Patcharee
authors.initials: P
authors.lastname: Ritprajak
authors.forename: Morisada
authors.initials: M
authors.lastname: Hayakawa
authors.forename: Yasuyo
authors.initials: Y
authors.lastname: Sano
authors.forename: Kinya
authors.initials: K
authors.lastname: Otsu
authors.forename: Jin Mo
authors.initials: JM
authors.lastname: Park
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D017931:DNA Primers / Q000235:genetics; D003713:Dendritic Cells / Q000378:metabolism*; D017449:Dermatitis, Allergic Contact / Q000276:immunology / Q000378:metabolism*; D004139:Dinitrofluorobenzene; D016503:Drug Delivery Systems / Q000379:methods; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006241:Haptens / Q000276:immunology / Q000494:pharmacology*; D015151:Immunoblotting; D015603:Keratinocytes / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D048308:Mitogen-Activated Protein Kinase 14 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D017931:DNA Primers; D006241:Haptens; D004139:Dinitrofluorobenzene; D048308:Mitogen-Activated Protein Kinase 14