title: An alternatively spliced IL-15 isoform modulates abrasion-induced keratinocyte activation.
abstract: In a routine phenotype-driven screen, we identified a point mutation in exon 7 of the IL-15 gene in Pedigree 191 (deficient memory (DM)) of N-ethyl-N-nitrosourea mutagenized mice. The DM epidermis expressed an alternatively spliced IL-15 mRNA isoform, IL-15ΔE7, and a wild-type (WT) IL-15 isoform at comparable levels. Mechanical stimulation of DM skin or DM skin graft transplanted onto the WT host resulted in reduced keratinocyte activation and inhibition of neutrophil infiltration into the dermis, demonstrating that DM keratinocytes produced less inflammatory response to external stimulation. Ectopic expression of IL-15ΔE7 in WT skin prevented abrasion-induced epidermal thickening, blocked the accumulation of nuclear antigen Ki67(+) cells in the basal and the suprabasal cell layers, increased loricrin expression, and also increased keratinocyte CXCL1 and G-CSF production. IL-15ΔE7 also profoundly blocked neutrophil infiltration in SDS- or immiquimod (IMQ)-treated WT skin. Recombinant IL-15ΔE7 failed to activate STAT-5 and its downstream target bcl-2 expression. Our study points to IL-15ΔE7 as a potential therapeutic agent for treating neutrophilia-associated inflammatory skin disorders.
authors.affiliation: The Graduate Institute of Immunology, National Taiwan University, College of Medicine, Taipei, Taiwan.
authors.forename: Tsung-Lin
authors.initials: TL
authors.lastname: Lee
authors.affiliation: The Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan.
authors.forename: Mei-Ling
authors.initials: ML
authors.lastname: Chang
authors.affiliation: The Graduate Institute of Immunology, National Taiwan University, College of Medicine, Taipei, Taiwan.
authors.forename: Yu-Jei
authors.initials: YJ
authors.lastname: Lin
authors.affiliation: The Graduate Institute of Immunology, National Taiwan University, College of Medicine, Taipei, Taiwan.
authors.forename: Ming-Hsun
authors.initials: MH
authors.lastname: Tsai
authors.affiliation: The Graduate Institute of Immunology, National Taiwan University, College of Medicine, Taipei, Taiwan.
authors.forename: Yi-Hsuan
authors.initials: YH
authors.lastname: Chang
authors.affiliation: The Graduate Institute of Immunology, National Taiwan University, College of Medicine, Taipei, Taiwan.
authors.forename: Che-Ming
authors.initials: CM
authors.lastname: Chuang
authors.affiliation: The Graduate Institute of Immunology, National Taiwan University, College of Medicine, Taipei, Taiwan.
authors.forename: Yun
authors.initials: Y
authors.lastname: Chien
authors.affiliation: Davidson Laboratory, Barbara Davis Center for Diabetes, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Sosinowski
authors.affiliation: The Graduate Institute of Immunology, National Taiwan University, College of Medicine, Taipei, Taiwan.
authors.forename: Chih-Hsiu
authors.initials: CH
authors.lastname: Wang
authors.affiliation: The Graduate Institute of Immunology, National Taiwan University, College of Medicine, Taipei, Taiwan.
authors.forename: Yi-Yuan
authors.initials: YY
authors.lastname: Chen
authors.affiliation: The Graduate Institute of Immunology, National Taiwan University, College of Medicine, Taipei, Taiwan.
authors.forename: Chien-Kuo
authors.initials: CK
authors.lastname: Lee
authors.affiliation: Department of Dermatology, National Taiwan University Hospital and National Taiwan University, College of Medicine, Taipei, Taiwan.
authors.forename: Jau-Shiuh
authors.initials: JS
authors.lastname: Chen
authors.affiliation: Department of Dermatology, National Taiwan University Hospital and National Taiwan University, College of Medicine, Taipei, Taiwan.
authors.forename: Li-Fang
authors.initials: LF
authors.lastname: Wang
authors.affiliation: The Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan. Electronic address: mbkung@ccvax.sinica.edu.tw.
authors.forename: John T
authors.initials: JT
authors.lastname: Kung
authors.affiliation: The Graduate Institute of Immunology, National Taiwan University, College of Medicine, Taipei, Taiwan. Electronic address: chiachiku@ntu.edu.tw.
authors.forename: Chia-Chi
authors.initials: CC
authors.lastname: Ku
mesh_terms: D017398:Alternative Splicing / Q000235:genetics / Q000502:physiology*; D000818:Animals; D002465:Cell Movement / Q000502:physiology; D049109:Cell Proliferation / Q000502:physiology; D054360:Chemokine CXCL1 / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor / Q000378:metabolism; D019409:Interleukin-15 / Q000235:genetics / Q000378:metabolism*; D015603:Keratinocytes / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000473:pathology; D017354:Point Mutation / Q000235:genetics; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D011565:Psoriasis / Q000378:metabolism* / Q000473:pathology*; D013314:Stress, Mechanical
chemical_list: D054360:Chemokine CXCL1; C475895:Cxcl1 protein, mouse; D019409:Interleukin-15; D008565:Membrane Proteins; D020033:Protein Isoforms; C064554:loricrin; D016179:Granulocyte Colony-Stimulating Factor