title: Susceptibility-associated genetic variation at IL12B enhances Th1 polarization in psoriasis.
abstract: The IL12B gene encodes the common p40 subunit of IL-12 and IL-23, cytokines with key roles in Th1 and Th17 biology, respectively, and genetic variation in this region significantly influences risk of psoriasis. Here, we demonstrate that a psoriasis-associated risk haplotype at the IL12B locus leads to increased expression of IL12B by monocytes and correlated with increased serum levels of IL-12, IFN-γ and the IFN-γ induced chemokine, CXCL10. In contrast, serum IL-23 levels were decreased in risk carriers when compared with non-carriers. We further demonstrate that IL-12 is increased in psoriatic skin and that risk carriers manifest a skewing of the inflammatory network toward stronger IFN-γ responses. Taken together, our data demonstrate that the risk variant in IL12B associates with its increased expression and predisposes to stronger Th1 polarization through deviation of the local inflammatory environment toward increased IL-12/IFN-γ at the expense of IL-23/IL-17 responses.
authors: Department of Dermatology, University of Michigan, Ann Arbor, MI 48109, USA.
authors: Andrew
authors: A
authors: Johnston
authors: Xianying
authors: X
authors: Xing
authors: William R
authors: WR
authors: Swindell
authors: James
authors: J
authors: Kochkodan
authors: Marybeth
authors: M
authors: Riblett
authors: Rajan P
authors: RP
authors: Nair
authors: Philip E
authors: PE
authors: Stuart
authors: Jun
authors: J
authors: Ding
authors: John J
authors: JJ
authors: Voorhees
authors: James T
authors: JT
authors: Elder
authors: Johann E
authors: JE
authors: Gudjonsson
mesh_terms: D000483:Alleles; D016022:Case-Control Studies; D002460:Cell Line; D054357:Chemokine CXCL10 / Q000097:blood; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006239:Haplotypes; D006801:Humans; D007371:Interferon-gamma / Q000097:blood; D053762:Interleukin-12 Subunit p40 / Q000235:genetics* / Q000378:metabolism; D020381:Interleukin-17 / Q000097:blood; D053759:Interleukin-23 / Q000097:blood; D015603:Keratinocytes / Q000378:metabolism; D009000:Monocytes / Q000276:immunology; D011565:Psoriasis / Q000235:genetics* / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012307:Risk Factors; D018417:Th1 Cells / Q000276:immunology*; D058504:Th17 Cells / Q000276:immunology; D015854:Up-Regulation
chemical_list: C114753:CXCL10 protein, human; D054357:Chemokine CXCL10; C500879:IL12B protein, human; D053762:Interleukin-12 Subunit p40; D020381:Interleukin-17; D053759:Interleukin-23; D012333:RNA, Messenger; D007371:Interferon-gamma
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