title: The Th2 cytokine, interleukin-4, abrogates the cohesion of normal stratum corneum in mice: implications for pathogenesis of atopic dermatitis.
abstract: There is mounting evidence that Th2 cytokines adversely affect skin barrier functions and contribute to the pathogenesis of atopic dermatitis (AD). AD is also characterized by abnormal cohesion in the stratum corneum (SC). However, the contribution of Th2 cytokines to this abnormality remains unknown. This study examined the effects of IL-4, a prototypic Th2 cytokine, on the cohesion of the SC. Structural and physiological assessments revealed that repeated intradermal injections of IL-4 compromised the cohesion of the SC of normal hairless mice. Two potential mechanisms were explored to account for the altered cohesion. First, IL-4 decreased the amount of corneodesmosomes and down-regulated the expression of desmoglein 1, but not of corneodesmosin (CDSN) or loricrin expression, in murine skin and in cultured human keratinocytes (KC). IL-4 did not affect the skin surface pH, and in situ zymography revealed no net change in total serine protease activity in the IL-4-treated SC. Yet, IL-4 enhanced expression of kallikrein (KLK)7, while simultaneously down-regulating KLK5 and KLK14. Finally, IL-4 did not alter the expression of the lympho-epithelial Kazal-type inhibitor (LEKTI) in KC. This study suggests that IL-4 abrogates the cohesion of SC primarily by reducing epidermal differentiation.
authors.affiliation: Department of Dermatology, Faculty of Medicine, Oita University, Yufu-shi, Oita, Japan. hatano@oita-u.ac.jp
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Hatano
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Adachi
authors.forename: Peter M
authors.initials: PM
authors.lastname: Elias
authors.forename: Debra
authors.initials: D
authors.lastname: Crumrine
authors.forename: Takashi
authors.initials: T
authors.lastname: Sakai
authors.forename: Rieko
authors.initials: R
authors.lastname: Kurahashi
authors.forename: Kazumoto
authors.initials: K
authors.lastname: Katagiri
authors.forename: Sakuhei
authors.initials: S
authors.lastname: Fujiwara
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D003876:Dermatitis, Atopic / Q000209:etiology*; D051183:Desmoglein 1 / Q000378:metabolism; D004817:Epidermis / Q000187:drug effects* / Q000378:metabolism* / Q000648:ultrastructure; D005260:Female; D006023:Glycoproteins / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D015847:Interleukin-4 / Q000494:pharmacology*; D007610:Kallikreins / Q000378:metabolism; D015603:Keratinocytes / Q000187:drug effects* / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D053491:Proteinase Inhibitory Proteins, Secretory / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D000074163:Serine Peptidase Inhibitor Kazal-Type 5; D057057:Serine Proteases / Q000378:metabolism
chemical_list: D000276:Adjuvants, Immunologic; C109656:CDSN protein, human; D051183:Desmoglein 1; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D053491:Proteinase Inhibitory Proteins, Secretory; D012333:RNA, Messenger; C120650:SPINK5 protein, human; D000074163:Serine Peptidase Inhibitor Kazal-Type 5; C529128:corneodesmosin protein, mouse; C064554:loricrin; D015847:Interleukin-4; D057057:Serine Proteases; C425336:KLK14 protein, human; C400147:KLK5 protein, human; C082472:KLK7 protein, human; D007610:Kallikreins; D002118:Calcium