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Here, we show that the effect of interfering with p38\u03b1 signaling can be therapeutic or adverse depending on the targeted cell type. Using a panel of mutant mice devoid of p38\u03b1 in distinct cell types and an experimental model of allergic skin disease, we find that dendritic cell (DC)-intrinsic p38\u03b1 function is crucial for both antigen-specific T-cell priming and T-cell\u2013mediated skin inflammation, two independent processes essential for the immunopathogenesis. By contrast, p38\u03b1 in other cell types serves to prevent excessive inflammation or maintain na\u00efve T-cell pools in the peripheral lymphoid tissues. These findings highlight a dilemma in the clinical use of p38\u03b1 inhibitors, yet also suggest cell-selective targeting as a potential solution for improving their therapeutic index.<\/jats:p>","DOI":"10.1073\/pnas.1202984109","type":"journal-article","created":{"date-parts":[[2012,5,21]],"date-time":"2012-05-21T23:03:58Z","timestamp":1337641438000},"page":"9089-9094","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":24,"title":["Cell type-specific targeting dissociates the therapeutic from the adverse effects of protein kinase inhibition in allergic skin disease"],"prefix":"10.1073","volume":"109","author":[{"given":"Patcharee","family":"Ritprajak","sequence":"first","affiliation":[{"name":"Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129;"},{"name":"Department of Microbiology and Immunology and Dental Research Unit of Oral Microbiology, Faculty of Dentistry, Chulalongkorn University, Patumwan, Bangkok 10330, Thailand;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Morisada","family":"Hayakawa","sequence":"additional","affiliation":[{"name":"Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasuyo","family":"Sano","sequence":"additional","affiliation":[{"name":"Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kinya","family":"Otsu","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan; and"},{"name":"Cardiovascular Division, King's College London, London SE5 9NU, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin Mo","family":"Park","sequence":"additional","affiliation":[{"name":"Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129;"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2012,5,21]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"crossref","first-page":"739","DOI":"10.1038\/372739a0","article-title":"A protein kinase involved in the regulation of inflammatory cytokine biosynthesis","volume":"372","author":"Lee JC","year":"1994","unstructured":"JC Lee, et al., A protein kinase involved in the regulation of inflammatory cytokine biosynthesis. 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Arthritis Rheum 60, 1232\u20131241 (2009).","journal-title":"Arthritis Rheum"},{"key":"e_1_3_4_7_2","doi-asserted-by":"crossref","first-page":"846","DOI":"10.3899\/jrheum.100602","article-title":"A 24-week, randomized, double-blind, placebo-controlled, parallel group study of the efficacy of oral SCIO-469, a p38 mitogen-activated protein kinase inhibitor, in patients with active rheumatoid arthritis","volume":"38","author":"Genovese MC","year":"2011","unstructured":"MC Genovese, et al., A 24-week, randomized, double-blind, placebo-controlled, parallel group study of the efficacy of oral SCIO-469, a p38 mitogen-activated protein kinase inhibitor, in patients with active rheumatoid arthritis. J Rheumatol 38, 846\u2013854 (2011).","journal-title":"J Rheumatol"},{"key":"e_1_3_4_8_2","doi-asserted-by":"crossref","first-page":"679","DOI":"10.1038\/nri2622","article-title":"Skin immune sentinels in health and disease","volume":"9","author":"Nestle FO","year":"2009","unstructured":"FO Nestle, P Di Meglio, JZ Qin, BJ Nickoloff, Skin immune sentinels in health and disease. Nat Rev Immunol 9, 679\u2013691 (2009).","journal-title":"Nat Rev Immunol"},{"key":"e_1_3_4_9_2","doi-asserted-by":"crossref","first-page":"958","DOI":"10.1038\/nri2448","article-title":"Exploring the full spectrum of macrophage activation","volume":"8","author":"Mosser DM","year":"2008","unstructured":"DM Mosser, JP Edwards, Exploring the full spectrum of macrophage activation. 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Nat Immunol 9, 1019\u20131027 (2008).","journal-title":"Nat Immunol"},{"key":"e_1_3_4_12_2","doi-asserted-by":"crossref","first-page":"3006","DOI":"10.1002\/eji.1830251103","article-title":"Major histocompatibility complex class I-restricted CD8+ T cells and class II-restricted CD4+ T cells, respectively, mediate and regulate contact sensitivity to dinitrofluorobenzene","volume":"25","author":"Bour H","year":"1995","unstructured":"H Bour, et al., Major histocompatibility complex class I-restricted CD8+ T cells and class II-restricted CD4+ T cells, respectively, mediate and regulate contact sensitivity to dinitrofluorobenzene. Eur J Immunol 25, 3006\u20133010 (1995).","journal-title":"Eur J Immunol"},{"key":"e_1_3_4_13_2","doi-asserted-by":"crossref","first-page":"1001","DOI":"10.1084\/jem.183.3.1001","article-title":"T cell populations primed by hapten sensitization in contact sensitivity are distinguished by polarized patterns of cytokine production: Interferon gamma-producing (Tc1) effector CD8+ T cells and interleukin (Il) 4\/Il-10-producing (Th2) negative regulatory CD4+ T cells","volume":"183","author":"Xu H","year":"1996","unstructured":"H Xu, NA DiIulio, RL Fairchild, T cell populations primed by hapten sensitization in contact sensitivity are distinguished by polarized patterns of cytokine production: Interferon gamma-producing (Tc1) effector CD8+ T cells and interleukin (Il) 4\/Il-10-producing (Th2) negative regulatory CD4+ T cells. J Exp Med 183, 1001\u20131012 (1996).","journal-title":"J Exp Med"},{"key":"e_1_3_4_14_2","doi-asserted-by":"crossref","first-page":"779","DOI":"10.1084\/jem.189.5.779","article-title":"Cytotoxicity is mandatory for CD8(+) T cell-mediated contact hypersensitivity","volume":"189","author":"Kehren J","year":"1999","unstructured":"J Kehren, et al., Cytotoxicity is mandatory for CD8(+) T cell-mediated contact hypersensitivity. J Exp Med 189, 779\u2013786 (1999).","journal-title":"J Exp Med"},{"key":"e_1_3_4_15_2","doi-asserted-by":"crossref","first-page":"260","DOI":"10.1046\/j.1523-1747.2000.00038.x","article-title":"Peptide immunization indicates that CD8+ T cells are the dominant effector cells in trinitrophenyl-specific contact hypersensitivity","volume":"115","author":"Martin S","year":"2000","unstructured":"S Martin, et al., Peptide immunization indicates that CD8+ T cells are the dominant effector cells in trinitrophenyl-specific contact hypersensitivity. J Invest Dermatol 115, 260\u2013266 (2000).","journal-title":"J Invest Dermatol"},{"key":"e_1_3_4_16_2","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1038\/nrm1834","article-title":"MAPKAP kinases - MKs - two\u2019s company, three\u2019s a crowd","volume":"7","author":"Gaestel M","year":"2006","unstructured":"M Gaestel, MAPKAP kinases - MKs - two\u2019s company, three\u2019s a crowd. Nat Rev Mol Cell Biol 7, 120\u2013130 (2006).","journal-title":"Nat Rev Mol Cell Biol"},{"key":"e_1_3_4_17_2","doi-asserted-by":"crossref","first-page":"2151","DOI":"10.1084\/jem.20070509","article-title":"Toll-like receptor and IL-12 signaling control susceptibility to contact hypersensitivity","volume":"205","author":"Martin SF","year":"2008","unstructured":"SF Martin, et al., Toll-like receptor and IL-12 signaling control susceptibility to contact hypersensitivity. 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J Immunol 181, 8576\u20138584 (2008).","journal-title":"J Immunol"},{"key":"e_1_3_4_21_2","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1038\/ni.1848","article-title":"Alternative cross-priming through CCL17-CCR4-mediated attraction of CTLs toward NKT cell-licensed DCs","volume":"11","author":"Semmling V","year":"2010","unstructured":"V Semmling, et al., Alternative cross-priming through CCL17-CCR4-mediated attraction of CTLs toward NKT cell-licensed DCs. Nat Immunol 11, 313\u2013320 (2010).","journal-title":"Nat Immunol"},{"key":"e_1_3_4_22_2","doi-asserted-by":"crossref","first-page":"8736","DOI":"10.1073\/pnas.0906126107","article-title":"Requirement of CCL17 for CCR7- and CXCR4-dependent migration of cutaneous dendritic cells","volume":"107","author":"Stutte S","year":"2010","unstructured":"S Stutte, et al., Requirement of CCL17 for CCR7- and CXCR4-dependent migration of cutaneous dendritic cells. Proc Natl Acad Sci USA 107, 8736\u20138741 (2010).","journal-title":"Proc Natl Acad Sci USA"},{"key":"e_1_3_4_23_2","doi-asserted-by":"crossref","first-page":"10611","DOI":"10.1128\/MCB.24.24.10611-10620.2004","article-title":"p38\u03b1 mitogen-activated protein kinase plays a critical role in cardiomyocyte survival but not in cardiac hypertrophic growth in response to pressure overload","volume":"24","author":"Nishida K","year":"2004","unstructured":"K Nishida, et al., p38\u03b1 mitogen-activated protein kinase plays a critical role in cardiomyocyte survival but not in cardiac hypertrophic growth in response to pressure overload. Mol Cell Biol 24, 10611\u201310620 (2004).","journal-title":"Mol Cell Biol"},{"key":"e_1_3_4_24_2","doi-asserted-by":"crossref","first-page":"1653","DOI":"10.1084\/jem.20062648","article-title":"Notch-RBP-J signaling controls the homeostasis of CD8- dendritic cells in the spleen","volume":"204","author":"Caton ML","year":"2007","unstructured":"ML Caton, MR Smith-Raska, B Reizis, Notch-RBP-J signaling controls the homeostasis of CD8- dendritic cells in the spleen. J Exp Med 204, 1653\u20131664 (2007).","journal-title":"J Exp Med"},{"key":"e_1_3_4_25_2","doi-asserted-by":"crossref","first-page":"12070","DOI":"10.1073\/pnas.92.26.12070","article-title":"T-cell-specific deletion of a polypeptide N-acetylgalactosaminyl-transferase gene by site-directed recombination","volume":"92","author":"Hennet T","year":"1995","unstructured":"T Hennet, FK Hagen, LA Tabak, JD Marth, T-cell-specific deletion of a polypeptide N-acetylgalactosaminyl-transferase gene by site-directed recombination. Proc Natl Acad Sci USA 92, 12070\u201312074 (1995).","journal-title":"Proc Natl Acad Sci USA"},{"key":"e_1_3_4_26_2","doi-asserted-by":"crossref","first-page":"1323","DOI":"10.1038\/mt.2008.91","article-title":"Topical application of cream-emulsified CD86 siRNA ameliorates allergic skin disease by targeting cutaneous dendritic cells","volume":"16","author":"Ritprajak P","year":"2008","unstructured":"P Ritprajak, M Hashiguchi, M Azuma, Topical application of cream-emulsified CD86 siRNA ameliorates allergic skin disease by targeting cutaneous dendritic cells. Mol Ther 16, 1323\u20131330 (2008).","journal-title":"Mol Ther"},{"key":"e_1_3_4_27_2","doi-asserted-by":"crossref","first-page":"4918","DOI":"10.4049\/jimmunol.0902478","article-title":"Keratinocyte-associated B7-H1 directly regulates cutaneous effector CD8+ T cell responses","volume":"184","author":"Ritprajak P","year":"2010","unstructured":"P Ritprajak, M Hashiguchi, F Tsushima, N Chalermsarp, M Azuma, Keratinocyte-associated B7-H1 directly regulates cutaneous effector CD8+ T cell responses. J Immunol 184, 4918\u20134925 (2010).","journal-title":"J Immunol"},{"key":"e_1_3_4_28_2","doi-asserted-by":"crossref","first-page":"1647","DOI":"10.1084\/jem.20041215","article-title":"Anthrolysin O and other gram-positive cytolysins are toll-like receptor 4 agonists","volume":"200","author":"Park JM","year":"2004","unstructured":"JM Park, VH Ng, S Maeda, RF Rest, M Karin, Anthrolysin O and other gram-positive cytolysins are toll-like receptor 4 agonists. 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