title: Alarmin function of cathelicidin antimicrobial peptide LL37 through IL-36γ induction in human epidermal keratinocytes.
abstract: Several dermatoses, including psoriasis, atopic dermatitis, and rosacea, alter the expression of the innate immune effector human cathelicidin antimicrobial peptide (CAMP). To elucidate the roles of aberrant CAMP in dermatoses, we performed cDNA array analysis in CAMP-stimulated human epidermal keratinocytes, the primary cells responding to innate immune stimuli and a major source of CAMP LL37 in skin. Among LL37-inducible genes, IL-1 cluster genes, particularly IL36G, are of interest because we observed coordinate increases in CAMP and IL-36γ in the lesional skin of psoriasis, whereas virtually no CAMP or IL-36γ was observed in nonlesional skin and normal skin. The production and release of IL-36γ were up to 20-30 ng/ml in differentiated keratinocytes cultured in high-calcium media. G-protein inhibitor pertussis toxin and p38 inhibitor suppressed IL-36γ induction by LL37. As an alarmin, LL37 induces chemokines, including CXCL1, CXCL8/IL8, CXCL10/IP-10, and CCL20/MIP3a, and IL-36 (10-100 ng/ml) augments the production of these chemokines by LL37. Pretreatment with small interfering RNA against IL36γ and IL-36R IL36R/IL1RL2 and IL1RAP suppressed LL37-dependent IL8, CXCL1, CXCL10/IP10, and CCL20 production in keratinocytes, suggesting that the alarmin function of LL37 was partially dependent on IL-36γ and its receptors. Counting on CAMP induction in innate stimuli, such as in infection and wounding, IL-36γ induction by cathelicidin would explain the mechanism of initiation of skin inflammation and occasional exacerbations of psoriasis and skin diseases by general infection.
authors.affiliation: Department of Dermatology, Graduate School of Medicine, Tohoku University, Sendai, Miyagi 980-8574, Japan; and.
authors.forename: Na
authors.initials: N
authors.lastname: Li
authors.affiliation: Department of Dermatology, Graduate School of Medicine, Tohoku University, Sendai, Miyagi 980-8574, Japan; and kyamasaki@med.tohoku.ac.jp.
authors.forename: Kenshi
authors.initials: K
authors.lastname: Yamasaki
authors.affiliation: Department of Dermatology, Graduate School of Medicine, Tohoku University, Sendai, Miyagi 980-8574, Japan; and Department of Integrative Genomics, Tohoku Medical Megabank Organization, Tohoku University, Sendai, Miyagi 980-8574, Japan.
authors.forename: Rumiko
authors.initials: R
authors.lastname: Saito
authors.affiliation: Department of Dermatology, Graduate School of Medicine, Tohoku University, Sendai, Miyagi 980-8574, Japan; and.
authors.forename: Sawako
authors.initials: S
authors.lastname: Fukushi-Takahashi
authors.affiliation: Department of Dermatology, Graduate School of Medicine, Tohoku University, Sendai, Miyagi 980-8574, Japan; and.
authors.forename: Ryoko
authors.initials: R
authors.lastname: Shimada-Omori
authors.affiliation: Department of Dermatology, Graduate School of Medicine, Tohoku University, Sendai, Miyagi 980-8574, Japan; and.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Asano
authors.affiliation: Department of Dermatology, Graduate School of Medicine, Tohoku University, Sendai, Miyagi 980-8574, Japan; and.
authors.forename: Setsuya
authors.initials: S
authors.lastname: Aiba
mesh_terms: D000595:Amino Acid Sequence; D023181:Antimicrobial Cationic Peptides; D002118:Calcium / Q000378:metabolism; D054804:Cathelicidins / Q000378:metabolism / Q000494:pharmacology*; D018925:Chemokines / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D003470:Culture Media / Q000737:chemistry; D005786:Gene Expression Regulation; D006801:Humans; D007375:Interleukin-1 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*; D015603:Keratinocytes / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D008969:Molecular Sequence Data; D037342:Pertussis Toxin / Q000494:pharmacology; D061251:Primary Cell Culture; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011565:Psoriasis / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D018121:Receptors, Cytokine / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction; D012867:Skin / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology
chemical_list: D023181:Antimicrobial Cationic Peptides; D054804:Cathelicidins; D018925:Chemokines; D003470:Culture Media; C508589:IL36G protein, human; D007375:Interleukin-1; D047428:Protein Kinase Inhibitors; D034741:RNA, Small Interfering; D018121:Receptors, Cytokine; D037342:Pertussis Toxin; D048051:p38 Mitogen-Activated Protein Kinases; D002118:Calcium