title: IFN-γ or IFN-α ameliorates chronic proliferative dermatitis by inducing expression of linear ubiquitin chain assembly complex.
abstract: The linear ubiquitin chain assembly complex (LUBAC) ubiquitin ligase complex, composed of HOIL-1L-interacting protein (HOIP), heme-oxidized IRP2 ubiquitin ligase-1L (HOIL-1L), and SHANK-associated RH domain protein, specifically generates linear polyubiquitin chains and is involved in NF-κB activation. Lack of SHANK-associated RH domain protein, which drastically reduces the amount of HOIP and HOIL-1L, causes chronic proliferative dermatitis (cpdm) in mice. Impaired NF-κB activation and augmented apoptosis have been implicated in the pathogenesis of cpdm in mice. In this study, we found that IFN-γ increased the amount of LUBAC by inducing HOIP and HOIL-1L mRNA transcription and enhanced the signal-induced NF-κB activation in embryonic fibroblasts, keratinocytes, and bone marrow-derived macrophages from wild-type and/or cpdm mice; however, IFN-γ failed to augment NF-κB activation in mouse embryonic fibroblasts lacking linear polyubiquitination activity of LUBAC. Moreover, s.c. injection of IFN-γ for 3 wk into the skin of cpdm mice increased the amount of HOIP, suppressed apoptosis, and ameliorated the dermatitis. Inhibition of keratinocyte apoptosis by IFN-γ injection suppressed neutrophil, macrophage, and mast cell infiltration and the amount of TNF-α in the skin of cpdm mice. Similarly, IFN-α also enhanced the amount of HOIP as well as NF-κB activation, inhibited apoptosis, and ameliorated cpdm dermatitis. These results indicate that the IFNs enhance NF-κB activation and ameliorate cpdm dermatitis by augmenting expression of HOIP and HOIL-1L and linear polyubiquitination activity of LUBAC.
authors.affiliation: Department of Molecular and Cellular Physiology, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan;
authors.forename: Hironari
authors.initials: H
authors.lastname: Tamiya
authors.forename: Mika
authors.initials: M
authors.lastname: Terao
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Takiuchi
authors.forename: Masaki
authors.initials: M
authors.lastname: Nakahara
authors.forename: Yoshiteru
authors.initials: Y
authors.lastname: Sasaki
authors.forename: Ichiro
authors.initials: I
authors.lastname: Katayama
authors.forename: Hideki
authors.initials: H
authors.lastname: Yoshikawa
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Iwai
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D002908:Chronic Disease; D003872:Dermatitis / Q000235:genetics* / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D016898:Interferon-alpha / Q000378:metabolism* / Q000494:pharmacology; D007371:Interferon-gamma / Q000008:administration & dosage / Q000378:metabolism* / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins; D008264:Macrophages / Q000473:pathology; D008407:Mast Cells / Q000473:pathology; D051379:Mice; D046912:Multiprotein Complexes / Q000235:genetics; D016328:NF-kappa B / Q000378:metabolism; D009504:Neutrophils / Q000473:pathology; D012867:Skin / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D044767:Ubiquitin-Protein Ligases / Q000235:genetics* / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D016898:Interferon-alpha; D007371:Interferon-gamma; D047908:Intracellular Signaling Peptides and Proteins; D046912:Multiprotein Complexes; D016328:NF-kappa B; D044767:Ubiquitin-Protein Ligases; C554944:Sipl1 protein, mouse; C492590:Rnf31 protein, mouse; C000607389:Rbck1 protein, mouse