title: Topically Administered Janus-Kinase Inhibitors Tofacitinib and Oclacitinib Display Impressive Antipruritic and Anti-Inflammatory Responses in a Model of Allergic Dermatitis.
abstract: The prevalence of allergic skin disorders has increased rapidly, and development of therapeutic agents to alleviate the symptoms are still needed. In this study, we orally or topically administered the Janus kinase (JAK) inhibitors, tofacitinib and oclacitinib, in a mouse model of dermatitis, and compared the efficacy to reduce the itch and inflammatory response. In vitro effects of JAK inhibitors on bone marrow-derived dendritic cells (BMDCs) were analyzed. For the allergic dermatitis model, female BALB/c mice were sensitized and challenged with toluene-2,4-diisocyanate (TDI). Each JAK inhibitor was orally or topically applied 30 minutes before and 4 hours after TDI challenge. After scratching bouts and ear thickness were measured, cytokines were determined in challenged skin and the cells of the draining lymph node were analyzed by means of flow cytometry. In vitro, both JAK inhibitors significantly inhibited cytokine production, migration, and maturation of BMDCs. Mice treated orally with JAK inhibitors showed a significant decrease in scratching behavior; however, ear thickness was not significantly reduced. In contrast, both scratching behavior and ear thickness in the topical treatment group were significantly reduced compared with the vehicle treatment group. However, cytokine production was differentially regulated by the JAK inhibitors, with some cytokines being significantly decreased and some being significantly increased. In conclusion, oral treatment with JAK inhibitors reduced itch behavior dramatically but had only little effect on the inflammatory response, whereas topical treatment improved both itch and inflammatory response. Although the JAK-inhibitory profile differs between both JAK inhibitors in vitro as well as in vivo, the effects have been comparable.
authors.affiliation: Department of Molecular Biomedical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, North Carolina.
authors.forename: Tomoki
authors.initials: T
authors.lastname: Fukuyama
authors.affiliation: Department of Molecular Biomedical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, North Carolina.
authors.forename: Sarah
authors.initials: S
authors.lastname: Ehling
authors.affiliation: Department of Molecular Biomedical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, North Carolina.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Cook
authors.affiliation: Department of Molecular Biomedical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, North Carolina wolfgang_baeumer@ncsu.edu.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Bäumer
mesh_terms: D000284:Administration, Oral; D000287:Administration, Topical; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage*; D000982:Antipruritics / Q000008:administration & dosage*; D016207:Cytokines / Q000378:metabolism; D017449:Dermatitis, Allergic Contact / Q000188:drug therapy* / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism; D053612:Janus Kinases / Q000037:antagonists & inhibitors*; D008198:Lymph Nodes / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D010880:Piperidines / Q000008:administration & dosage*; D011537:Pruritus / Q000188:drug therapy / Q000378:metabolism; D011743:Pyrimidines / Q000008:administration & dosage*; D011758:Pyrroles / Q000008:administration & dosage*; D012867:Skin / Q000187:drug effects / Q000378:metabolism; D013449:Sulfonamides / Q000008:administration & dosage*
chemical_list: D000893:Anti-Inflammatory Agents; D000982:Antipruritics; D016207:Cytokines; D010880:Piperidines; D011743:Pyrimidines; D011758:Pyrroles; D013449:Sulfonamides; C479163:tofacitinib; C588062:oclacitinib; D053612:Janus Kinases