title: Lupus Skin Is Primed for IL-6 Inflammatory Responses through a Keratinocyte-Mediated Autocrine Type I Interferon Loop.
abstract: Cutaneous lupus erythematosus is a disfiguring and common manifestation in systemic lupus erythematosus, and the etiology of this predisposition for cutaneous inflammation is unknown. Here, we sought to examine the keratinocyte as an important source of IL-6 and define the mechanism for its increased production in cutaneous lupus erythematosus. Evaluation of discoid and subacute cutaneous lupus erythematosus lesions showed significant epidermal up-regulation of IL-6 compared with control via real-time PCR and immunohistochemistry. Keratinocytes from unaffected skin of lupus patients produced significantly more IL-6 compared with healthy control subjects after exposure to toll-like receptor 2, 3, or 4 agonists or exposure to UVB radiation. Pretreatment with type I interferons (IFN-α and IFN-κ) increased IL-6 production by control keratinocytes, and type I IFN blockade decreased IL-6 secretion by lupus keratinocytes. Secretion of keratinocyte-specific IFN-κ was significantly increased after toll-like receptor 2 and UVB treatment in lupus keratinocytes, and neutralization of IFN-κ decreased IL-6 production by lupus keratinocytes. Thus, lupus keratinocytes are primed for IL-6 hyperproduction in a type I IFN-dependent manner. Increased production of IFN-κ by lupus keratinocytes drives this response, indicating that IFN-κ may play a pathogenic role in cutaneous lupus erythematosus and serve as a target for treatment.
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA; Division of Rheumatology, Department of Pediatrics, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Jasmine N
authors.initials: JN
authors.lastname: Stannard
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Tamra J
authors.initials: TJ
authors.lastname: Reed
authors.affiliation: Division of Rheumatology, Department of Medicine, MedStar Georgetown University Hospital, Washington, District of Columbia, USA.
authors.forename: Emily
authors.initials: E
authors.lastname: Myers
authors.affiliation: Department of Dermatology, University of Michigan, Ann Arbor, Michigan, USA; Department of Pathology, University of Michigan, Ann Arbor, Michigan USA.
authors.forename: Lori
authors.initials: L
authors.lastname: Lowe
authors.affiliation: Department of Dermatology, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Mrinal K
authors.initials: MK
authors.lastname: Sarkar
authors.affiliation: Department of Dermatology, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Xianying
authors.initials: X
authors.lastname: Xing
authors.affiliation: Department of Dermatology, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Johann E
authors.initials: JE
authors.lastname: Gudjonsson
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA. Electronic address: mkahlenb@med.umich.edu.
authors.forename: J Michelle
authors.initials: JM
authors.lastname: Kahlenberg
mesh_terms: D000328:Adult; D001707:Biopsy, Needle; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D015850:Interleukin-6 / Q000276:immunology / Q000378:metabolism*; D015603:Keratinocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D008178:Lupus Erythematosus, Cutaneous / Q000276:immunology* / Q000473:pathology; D008179:Lupus Erythematosus, Discoid / Q000276:immunology* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D012313:RNA / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction / Q000379:methods; D012494:Sampling Studies; D018709:Statistics, Nonparametric; D051193:Toll-Like Receptors / Q000008:administration & dosage / Q000037:antagonists & inhibitors*; D014466:Ultraviolet Rays / Q000009:adverse effects
chemical_list: D015850:Interleukin-6; D051193:Toll-Like Receptors; D012313:RNA