title: ASK1 promotes the contact hypersensitivity response through IL-17 production.
abstract: Contact hypersensitivity (CHS) is a form of delayed-type hypersensitivity triggered by the response to reactive haptens (sensitization) and subsequent challenge (elicitation). Here, we show that ASK1 promotes CHS and that suppression of ASK1 during the elicitation phase is sufficient to attenuate CHS. ASK1 knockout (KO) mice exhibited impaired 2,4-dinitrofluorobenzene (DNFB)-induced CHS. The suppression of ASK1 activity during the elicitation phase through a chemical genetic approach or a specific inhibitory compound significantly reduced the CHS response to a level similar to that observed in ASK1 KO mice. The reduced response was concomitant with the strong inhibition of production of IL-17, a cytokine that plays an important role in CHS and other inflammatory diseases, from sensitized lymph node cells. These results suggest that ASK1 is relevant to the overall CHS response during the elicitation phase and that ASK1 may be a promising therapeutic target for allergic contact dermatitis and other IL-17-related inflammatory diseases.
authors.affiliation: 1] Laboratory of Cell Signaling, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, Japan, 113-0033 [2] Department of Dermatology, Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo, Japan, 160-0023.
authors.forename: Junya
authors.initials: J
authors.lastname: Mizukami
authors.affiliation: Laboratory of Cell Signaling, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, Japan, 113-0033.
authors.forename: Takehiro
authors.initials: T
authors.lastname: Sato
authors.affiliation: Departments of Inflammation, Merck Serono International S.A., 1202 Geneva, Switzerland.
authors.forename: Montserrat
authors.initials: M
authors.lastname: Camps
authors.affiliation: Novo Nordisk A/S, Novo Nordisk Park, DK-2760 Måløv, Denmark.
authors.forename: Hong
authors.initials: H
authors.lastname: Ji
authors.affiliation: Medicines for Malaria Venture, Department of Translational Medicine, Route de Pré-Bois 20, CH-1215 Geneva, Switzerland.
authors.forename: Thomas
authors.initials: T
authors.lastname: Rueckle
authors.affiliation: Department of Chemistry, Merck Serono International S.A., 1202 Geneva, Switzerland.
authors.forename: Dominique
authors.initials: D
authors.lastname: Swinnen
authors.affiliation: Department of Dermatology, Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo, Japan, 160-0023.
authors.forename: Ryoji
authors.initials: R
authors.lastname: Tsuboi
authors.affiliation: 1] Laboratory of Cell Signaling, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, Japan, 113-0033 [2] Division of Cell Regulation, Graduate School of Biomedical Sciences, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan.
authors.forename: Kohsuke
authors.initials: K
authors.lastname: Takeda
authors.affiliation: Laboratory of Cell Signaling, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, Japan, 113-0033.
authors.forename: Hidenori
authors.initials: H
authors.lastname: Ichijo
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D003877:Dermatitis, Contact / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D004139:Dinitrofluorobenzene / Q000633:toxicity; D004195:Disease Models, Animal; D057809:HEK293 Cells; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D020381:Interleukin-17 / Q000235:genetics / Q000378:metabolism*; D048848:MAP Kinase Kinase Kinase 5 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D020381:Interleukin-17; D007371:Interferon-gamma; D004139:Dinitrofluorobenzene; D048051:p38 Mitogen-Activated Protein Kinases; D048848:MAP Kinase Kinase Kinase 5; C482859:Map3k5 protein, mouse
references.citation: J Immunol. 2009 Jul 15;183(2):1463-70
references.pmid: 19553527
references.citation: J Exp Med. 2007 Dec 24;204(13):3147-56
references.pmid: 18086865
references.citation: J Allergy Clin Immunol. 2010 May;125(5):1154-1156.e2
references.pmid: 20226508
references.citation: J Immunol. 2001 Mar 15;166(6):3837-45
references.pmid: 11238627
references.citation: Immunol Rev. 2008 Dec;226:57-79
references.pmid: 19161416
references.citation: Nat Immunol. 2005 Jun;6(6):587-92
references.pmid: 15864310
references.citation: Cancer Sci. 2012 Dec;103(12):2181-5
references.pmid: 23110662
references.citation: Annu Rev Immunol. 2009;27:485-517
references.pmid: 19132915
references.citation: Proc Natl Acad Sci U S A. 2003 Apr 1;100(7):4287-92
references.pmid: 12646704
references.citation: Immunol Today. 1998 Jan;19(1):37-44
references.pmid: 9465487
references.citation: J Biol Chem. 2002 Oct 4;277(40):37896-903
references.pmid: 12138127
references.citation: J Exp Med. 2007 Dec 24;204(13):3133-46
references.pmid: 18086862
references.citation: J Invest Dermatol. 1999 Apr;112(4):476-82
references.pmid: 10201532
references.citation: Annu Rev Pharmacol Toxicol. 2008;48:199-225
references.pmid: 17883330
references.citation: Science. 1997 Jan 3;275(5296):90-4
references.pmid: 8974401
references.citation: J Invest Dermatol. 2003 Mar;120(3):390-9
references.pmid: 12603851
references.citation: EMBO J. 2009 Apr 8;28(7):843-53
references.pmid: 19214184
references.citation: J Invest Dermatol. 2010 Dec;130(12):2752-9
references.pmid: 20703247
references.citation: J Cell Physiol. 2002 Apr;191(1):95-104
references.pmid: 11920685
references.citation: Immunology. 1999 Sep;98(1):71-9
references.pmid: 10469236
references.citation: EMBO J. 1998 May 1;17(9):2596-606
references.pmid: 9564042
references.citation: Immunity. 2002 Sep;17(3):375-87
references.pmid: 12354389
references.citation: Scand J Immunol. 1997 Mar;45(3):308-14
references.pmid: 9122622
references.citation: J Exp Med. 1995 Jul 1;182(1):99-108
references.pmid: 7790826
references.citation: Drug Discov Today. 2002 Aug 15;7(16):872-9
references.pmid: 12546954
references.citation: J Biol Chem. 2007 Mar 9;282(10):7522-31
references.pmid: 17210579
references.citation: EMBO Rep. 2001 Mar;2(3):222-8
references.pmid: 11266364
references.citation: Allergol Int. 2008 Jun;57(2):121-34
references.pmid: 18427165
references.citation: J Immunol. 2006 Nov 15;177(10):6852-8
references.pmid: 17082599
references.citation: APMIS. 2012 Jan;120(1):1-27
references.pmid: 22151305
references.citation: Blood. 2011 Sep 22;118(12):3290-300
references.pmid: 21791428
references.citation: Cell Mol Life Sci. 2012 Mar;69(5):763-81
references.pmid: 21997384
references.citation: EMBO Mol Med. 2010 Dec;2(12):504-15
references.pmid: 21064192
references.citation: Immunity. 2005 May;22(5):643-54
references.pmid: 15894281
references.citation: Science. 1999 Apr 30;284(5415):819-22
references.pmid: 10221917
references.citation: Nat Methods. 2005 Jun;2(6):435-41
references.pmid: 15908922