RGD Reference Report - Keratinocyte overexpression of IL-17C promotes psoriasiform skin inflammation. - Rat Genome Database

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Keratinocyte overexpression of IL-17C promotes psoriasiform skin inflammation.

Authors: Johnston, A  Fritz, Y  Dawes, SM  Diaconu, D  Al-Attar, PM  Guzman, AM  Chen, CS  Fu, W  Gudjonsson, JE  McCormick, TS  Ward, NL 
Citation: Johnston A, etal., J Immunol. 2013 Mar 1;190(5):2252-62. doi: 10.4049/jimmunol.1201505. Epub 2013 Jan 28.
RGD ID: 8698663
Pubmed: PMID:23359500   (View Abstract at PubMed)
PMCID: PMC3577967   (View Article at PubMed Central)
DOI: DOI:10.4049/jimmunol.1201505   (Journal Full-text)

IL-17C is a functionally distinct member of the IL-17 family that binds IL-17 receptor E/A to promote innate defense in epithelial cells and regulate Th17 cell differentiation. We demonstrate that IL-17C (not IL-17A) is the most abundant IL-17 isoform in lesional psoriasis skin (1058 versus 8 pg/ml; p < 0.006) and localizes to keratinocytes (KCs), endothelial cells (ECs), and leukocytes. ECs stimulated with IL-17C produce increased TNF-alpha and KCs stimulated with IL-17C/TNF-alpha produce similar inflammatory gene response patterns as those elicited by IL-17A/TNF-alpha, including increases in IL-17C, TNF-alpha, IL-8, IL-1alpha/beta, IL-1F5, IL-1F9, IL-6, IL-19, CCL20, S100A7/A8/A9, DEFB4, lipocalin 2, and peptidase inhibitor 3 (p < 0.05), indicating a positive proinflammatory feedback loop between the epidermis and ECs. Psoriasis patients treated with etanercept rapidly decrease cutaneous IL-17C levels, suggesting IL-17C/TNF-alpha-mediated inflammatory signaling is critical for psoriasis pathogenesis. Mice genetically engineered to overexpress IL-17C in KCs develop well-demarcated areas of erythematous, flakey involved skin adjacent to areas of normal-appearing uninvolved skin despite increased IL-17C expression in both areas (p < 0.05). Uninvolved skin displays increased angiogenesis and elevated S100A8/A9 expression (p < 0.05) but no epidermal hyperplasia, whereas involved skin exhibits robust epidermal hyperplasia, increased angiogenesis and leukocyte infiltration, and upregulated TNF-alpha, IL-1alpha/beta, IL-17A/F, IL-23p19, vascular endothelial growth factor, IL-6, and CCL20 (p < 0.05), suggesting that IL-17C, when coupled with other proinflammatory signals, initiates the development of psoriasiform dermatitis. This skin phenotype was significantly improved following 8 wk of TNF-alpha inhibition. These findings identify a role for IL-17C in skin inflammation and suggest a pathogenic function for the elevated IL-17C observed in lesional psoriasis skin.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
psoriasis  ISOIl17a (Mus musculus)8698663; 8698663mRNA:protein:increased expression:epidermis (human)RGD 
psoriasis  IEP 8698663; 8698663mRNA:protein:increased expression:epidermis (human)RGD 
psoriasis  ISOIL17A (Homo sapiens)8698663; 8698663mRNA:protein:increased expression:epidermis (human)RGD 

Objects Annotated

Genes (Rattus norvegicus)
Il17a  (interleukin 17A)

Genes (Mus musculus)
Il17a  (interleukin 17A)

Genes (Homo sapiens)
IL17A  (interleukin 17A)


Additional Information