title: Human antimicrobial peptide LL-37 modulates proinflammatory responses induced by cytokine milieus and double-stranded RNA in human keratinocytes.
abstract: Epidermal keratinocytes produce proinflammatory cytokines/chemokines upon stimulation with cytokine milieus and Toll-like receptor ligands, which are considered to reflect epidermal environments in inflamed skin. The human antimicrobial peptide LL-37, besides having microbicidal functions, plays multiple roles as a "host defense peptide" in the immune system. Here, we examined the effect of LL-37 on proinflammatory responses induced by double-stranded RNA (dsRNA) and cytokines in primary human keratinocytes. LL-37 inhibited dsRNA-induced production of thymic stromal lymphopoietin (TSLP), CCL5/RANTES, CXCL10/IP-10, and CXCL8/IL-8, which was attributable to interaction between LL-37 and dsRNA, although LL-37 upregulated CXCL8 expression at an earlier time point (8 h). LL-37 inhibited the increase of CXCL10 and CCL5 induced by TNF-α- and/or IFN-γ but enhanced that of CXCL8. LL-37 and Th17 cytokines (IL-17 and IL-22) synergistically upregulated the expression of CXCL8 and IL-6. LL-37 showed the effects above at a high concentration (25 μg/ml, 5.6 μM). We also examined effects of a peptide with a scrambled LL-37 sequence, which has been frequently used as a negative control, and those of another peptide with the reversed LL-37 sequence, activities of which have not been well investigated. Interestingly, the reversed LL-37 had effects similar to LL-37 but the scrambled LL-37 did not. The modulation by LL-37 of the keratinocyte proinflammatory responses induced by cytokine milieus and dsRNA suggests novel roles for LL-37 in skin inflammation such as the promotion of IL17/IL-22/IL-6-associated psoriasis and suppression of TSLP-associated atopic dermatitis.
authors.affiliation: Atopy (Allergy) Research Center, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan.
authors.forename: Xue
authors.initials: X
authors.lastname: Chen
authors.forename: Toshiro
authors.initials: T
authors.lastname: Takai
authors.forename: Yang
authors.initials: Y
authors.lastname: Xie
authors.forename: François
authors.initials: F
authors.lastname: Niyonsaba
authors.forename: Ko
authors.initials: K
authors.lastname: Okumura
authors.forename: Hideoki
authors.initials: H
authors.lastname: Ogawa
mesh_terms: D000595:Amino Acid Sequence; D000893:Anti-Inflammatory Agents / Q000276:immunology / Q000494:pharmacology; D023181:Antimicrobial Cationic Peptides / Q000276:immunology* / Q000494:pharmacology; D002478:Cells, Cultured; D018946:Chemokine CCL5 / Q000276:immunology; D054357:Chemokine CXCL10 / Q000276:immunology; D016207:Cytokines / Q000235:genetics / Q000276:immunology; D003876:Dermatitis, Atopic / Q000276:immunology / Q000473:pathology; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology / Q000494:pharmacology; D015850:Interleukin-6 / Q000276:immunology; D016209:Interleukin-8 / Q000276:immunology; D007378:Interleukins / Q000276:immunology / Q000494:pharmacology; D015603:Keratinocytes / Q000187:drug effects* / Q000276:immunology* / Q000473:pathology; D008969:Molecular Sequence Data; D061251:Primary Cell Culture; D011565:Psoriasis / Q000276:immunology / Q000473:pathology; D012330:RNA, Double-Stranded / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000276:immunology; D058504:Th17 Cells / Q000187:drug effects / Q000276:immunology; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000494:pharmacology; D054804:Cathelicidins; D000094632:Thymic Stromal Lymphopoietin; D000097043:Interleukin-22
chemical_list: D000893:Anti-Inflammatory Agents; D023181:Antimicrobial Cationic Peptides; D018946:Chemokine CCL5; D054357:Chemokine CXCL10; D016207:Cytokines; D007371:Interferon-gamma; D015850:Interleukin-6; D016209:Interleukin-8; D007378:Interleukins; D012330:RNA, Double-Stranded; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D054804:Cathelicidins; D000094632:Thymic Stromal Lymphopoietin; D000097043:Interleukin-22; C483024:CCL5 protein, human; C114753:CXCL10 protein, human; C508606:CXCL8 protein, human; C508600:IL6 protein, human