IFNλ Stimulates MxA Production in Human Dermal Fibroblasts via a MAPK-Dependent STAT1-Independent Mechanism.
IFNλ is important for epidermal defense against viruses. It is produced by, and acts on, keratinocytes, whereas fibroblasts were previously considered to be unresponsive to this type III IFN. Herein we report findings revealing cell type-specific differences in IFNλ signaling and function in skin resident cells. In dermal fibroblasts, IFNλ induced the expression of myxovirus protein A (MxA), a potent antiviral factor, but not other IFN signature genes as it does in primary keratinocytes. In contrast to its effect on keratinocytes, IFNλ did not phosphorylate signal transducer and activator of transcription 1 in fibroblasts, but instead activated mitogen activated protein kinases (MAPK). Accordingly, inhibition of MAPK activation (p38 and p42/44) blocked the expression of MxA protein in fibroblasts but not in keratinocytes. Functionally, IFNλ inhibited proliferation in keratinocytes but not in fibroblasts. Moreover, IFNλ upregulated the expression of Tumor growth factor beta 1 (TGFβ1)-induced collagens in fibroblasts. Taken together, our findings identify primary human dermal fibroblasts as responder cells to IFNλ. Our study shows cutaneous cell type-specific IFN signaling and suggests that IFNλ, although important for epidermal antiviral competence, may also have a regulatory role in the dermal compartment balancing type I IFN-induced inhibition of tissue repair processes.
Centre for Skin Sciences, Faculty of Life Sciences, University of Bradford, Bradford, UK. Electronic address: a.a.alase@student.bradford.ac.uk.
Adewonuola A
AA
Alase
Leeds Institute of Rheumatic and Musculoskeletal Medicine (LIRMM), Faculty of Medicine and Health, University of Leeds, Leeds, UK; Clinical Pathology Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt.
Yasser M
YM
El-Sherbiny
Leeds Institute of Rheumatic and Musculoskeletal Medicine (LIRMM), Faculty of Medicine and Health, University of Leeds, Leeds, UK.
Edward M
EM
Vital
Centre for Skin Sciences, Faculty of Life Sciences, University of Bradford, Bradford, UK.
Desmond J
DJ
Tobin
Division of Cardiovascular and Diabetes Research, Leeds Institute for Cardiovascular and Diabetes Research (LICAMM), Faculty of Medicine and Health, University of Leeds, Leeds, UK.
Neil A
NA
Turner
Centre for Skin Sciences, Faculty of Life Sciences, University of Bradford, Bradford, UK; Leeds Institute of Rheumatic and Musculoskeletal Medicine (LIRMM), Faculty of Medicine and Health, University of Leeds, Leeds, UK; Department of Dermatology, Bradford Teaching Hospitals NHS Foundation Trust, St Luke's Hospital, Bradford, UK; Leeds Musculoskeletal Biomedical Research Unit, National Institute of Health Research (NIHR), Chapel Allerton Hospital, Leeds, UK.
Miriam
M
Wittmann
D002478:Cells, Cultured; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology; D007371:Interferon-gamma / Q000494:pharmacology*; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology*; D064547:Myxovirus Resistance Proteins / Q000096:biosynthesis*; D017471:Receptors, Interferon / Q000502:physiology; D050794:STAT1 Transcription Factor / Q000502:physiology*; D012867:Skin / Q000166:cytology / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology; D000096743:Interferon gamma Receptor
D016898:Interferon-alpha; D007371:Interferon-gamma; D020928:Mitogen-Activated Protein Kinases; D064547:Myxovirus Resistance Proteins; D017471:Receptors, Interferon; D050794:STAT1 Transcription Factor; D053773:Transforming Growth Factor beta1; D000096743:Interferon gamma Receptor; C579071:MX1 protein, human; C494079:STAT1 protein, human