title: Poly(I:C) induces controlled release of IL-36γ from keratinocytes in the absence of cell death.
abstract: The epithelium is part of an integrated immune system where cytokines, toll-like receptors and their ligands, and extracellular vesicles play a crucial role in initiating an innate immune response. IL-36γ is a pro-inflammatory member of the IL-1 family that is mainly expressed by epithelial cells, but regulation of its expression and release are only beginning to be understood. Previous studies reported that IL-36γ is abundant in recurrent respiratory papillomatosis, a rare but devastating disease caused by human papillomaviruses (HPV) types 6 and 11, in which papillomas recurrently grow in and block the airway. Despite the overexpression of IL-36γ, papilloma tissues show no evidence of inflammation, possibly due to suppression of its release by HPVs. We have used primary human foreskin keratinocytes as a model to study IL-36γ regulation in normal epithelial cells. Low doses of poly(I:C) mediate expression and release of IL-36γ without inducing the cell death reported by those using high doses. PKR, an enzyme required for inflammasome activation, does not contribute to controlled release of IL36γ. The keratinocytes secrete IL-36γ in two forms, soluble and in extracellular vesicles. We conclude that there are two separately regulated pathways for the controlled secretion of IL-36γ from keratinocytes, which could contribute to the modulation of both local and systemic immune responses to viruses and other pathogens.
authors.affiliation: The Elmezzi Graduate School of Molecular Medicine, 350 Community Drive, Manhasset, NY, 11030, USA.|The Feinstein Institute for Medical Research, 350 Community Drive, Manhasset, NY, 11030, USA.
authors.forename: Ali A
authors.initials: AA
authors.lastname: Rana
authors.affiliation: The Feinstein Institute for Medical Research, 350 Community Drive, Manhasset, NY, 11030, USA.
authors.forename: Alexandra V
authors.initials: AV
authors.lastname: Lucs
authors.affiliation: The Feinstein Institute for Medical Research, 350 Community Drive, Manhasset, NY, 11030, USA.
authors.forename: James
authors.initials: J
authors.lastname: DeVoti
authors.affiliation: The Elmezzi Graduate School of Molecular Medicine, 350 Community Drive, Manhasset, NY, 11030, USA.|The Feinstein Institute for Medical Research, 350 Community Drive, Manhasset, NY, 11030, USA.|Department of Molecular Medicine, Hofstra North Shore LIJ School of Medicine, 350 Community Drive, Manhasset, NY, 11030, USA.|Department of Otolaryngology and Communication Disorders, Hofstra North Shore LIJ School of Medicine, Hearing and Speech Center, 430 Lakeville Road, New Hyde Park, NY, 11040, USA.
authors.forename: Lionel
authors.initials: L
authors.lastname: Blanc
authors.affiliation: The Feinstein Institute for Medical Research, 350 Community Drive, Manhasset, NY, 11030, USA.
authors.forename: Julien
authors.initials: J
authors.lastname: Papoin
authors.affiliation: The Feinstein Institute for Medical Research, 350 Community Drive, Manhasset, NY, 11030, USA.
authors.forename: Rong
authors.initials: R
authors.lastname: Wu
authors.affiliation: The Feinstein Institute for Medical Research, 350 Community Drive, Manhasset, NY, 11030, USA.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Papayannakos
authors.affiliation: The Feinstein Institute for Medical Research, 350 Community Drive, Manhasset, NY, 11030, USA.|Department of Otolaryngology and Communication Disorders, Hofstra North Shore LIJ School of Medicine, Hearing and Speech Center, 430 Lakeville Road, New Hyde Park, NY, 11040, USA.
authors.forename: Allan
authors.initials: A
authors.lastname: Abramson
authors.affiliation: The Elmezzi Graduate School of Molecular Medicine, 350 Community Drive, Manhasset, NY, 11030, USA.|The Feinstein Institute for Medical Research, 350 Community Drive, Manhasset, NY, 11030, USA.|Division of Allergy and Immunology, Department of Pediatrics, Hofstra North Shore-LIJ School of Medicine, 865 Northern Blvd, Great Neck, NY, 11021, USA.
authors.forename: Vincent R
authors.initials: VR
authors.lastname: Bonagura
authors.affiliation: The Elmezzi Graduate School of Molecular Medicine, 350 Community Drive, Manhasset, NY, 11030, USA. bsteinbe@lij.edu.|The Feinstein Institute for Medical Research, 350 Community Drive, Manhasset, NY, 11030, USA. bsteinbe@lij.edu.|Department of Molecular Medicine, Hofstra North Shore LIJ School of Medicine, 350 Community Drive, Manhasset, NY, 11030, USA. bsteinbe@lij.edu.
authors.forename: Bettie M
authors.initials: BM
authors.lastname: Steinberg
mesh_terms: D016923:Cell Death; D045744:Cell Line, Tumor; D000067128:Extracellular Vesicles / Q000378:metabolism*; D006801:Humans; D007375:Interleukin-1 / Q000378:metabolism*; D015603:Keratinocytes / Q000276:immunology*; D008175:Lung Neoplasms / Q000276:immunology*; D008297:Male; D010212:Papilloma / Q000276:immunology*; D011070:Poly I-C / Q000276:immunology*; D019892:eIF-2 Kinase / Q000378:metabolism
chemical_list: C508589:IL36G protein, human; D007375:Interleukin-1; D019892:eIF-2 Kinase; D011070:Poly I-C
keywords: Cytokines; IL-36γ; Keratinocytes; Papilloma; TLR3