Qian Y, Liu C, Hartupee J et al.The adaptor Act1 is required for interleukin 17-dependent signaling associated with autoimmune and inflammatory disease. Nat Immunol 8:247-256

Department of Immunology, Cleveland Clinic, Cleveland, Ohio 44195, USA.
Nature Immunology (Impact Factor: 20). 04/2007; 8(3):247-56. DOI: 10.1038/ni1439
Source: PubMed

ABSTRACT T helper cells that produce interleukin 17 (IL-17) are associated with inflammation and the control of certain bacteria. We report here the essential involvement of the adaptor protein Act1 in IL-17 receptor (IL-17R) signaling and IL-17-dependent immune responses. After stimulation with IL-17, recruitment of Act1 to IL-17R required the IL-17R conserved cytoplasmic 'SEFIR' domain, followed by recruitment of the kinase TAK1 and E3 ubiquitin ligase TRAF6, which mediate 'downstream' activation of transcription factor NF-kappaB. IL-17-induced expression of inflammation-related genes was abolished in Act1-deficient primary astroglial and gut epithelial cells. This reduction was associated with much less inflammatory disease in vivo in both autoimmune encephalomyelitis and dextran sodium sulfate-induced colitis. Our data show that Act1 is essential in IL-17-dependent signaling in autoimmune and inflammatory disease.

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Available from: Bruce A Vallance, Mar 28, 2014
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    • "Because IL-17 is important in experimental autoimmune encephalomyelitis (EAE) pathogenesis, a model of multiple sclerosis, the effect of Act1 was assessed on a mouse model of EAE. Interestingly, Act1-deficient mice showed a delay in the onset of neurological impairment and had much lower severity compared to wild-type mice (151). "
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    ABSTRACT: Autoimmune diseases are characterized by the production of antibodies against self-antigens and generally arise from a failure of central or peripheral tolerance. However, these diseases may develop when newly appearing antigens are not recognized as self by the immune system. The mechanism by which some antigens are "invisible" to the immune system is not completely understood. Apoptotic and complement system defects or autophagy imbalance can generate this antigenic autoreactivity. Under particular circumstances, cellular debris containing autoreactive antigens can be recognized by innate immune receptors or other sensors and can eventually lead to autoimmunity. Ubiquitination may be one of the mechanisms protecting autoreactive antigens from the immune system that, if disrupted, can lead to autoimmunity. Ubiquitination is an essential post-translational modification used by cells to target proteins for degradation or to regulate other intracellular processes. The level of ubiquitination is regulated during T cell tolerance and apoptosis and E3 ligases have emerged as a crucial signaling pathway for the regulation of T cell tolerance toward self-antigens. I propose here that an unrecognized role of ubiquitin and ubiquitin-like proteins could be to render intracellular or foreign antigens (present in cellular debris resulting from apoptosis, complement system, or autophagy defects) invisible to the immune system in order to prevent the development of autoimmunity.
    Frontiers in Immunology 06/2014; 5:262. DOI:10.3389/fimmu.2014.00262
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    • "IL-17A signals through a heteromeric receptor complex, consisting of IL-17R (IL-17RA) and IL-17RC, which are single-pass transmembrane proteins and ubiquitously expressed in various cell types including epithelial cells and fibroblasts [29]. Recently, a novel signaling molecule, act1, was found to be a key component in IL-17A signaling [30]. The act1 gene was first cloned as an NF-κB activator. "
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    ABSTRACT: Background Recent studies demonstrated that nasal polyps (NP) patients in China and other Asian regions possessed distinct Th17-dominant inflammation and enhanced tissue remodeling. However, the mechanism underlying these observations is not fully understood. This study sought to evaluate the association of interleukin (IL)-17A with MUC5AC expression and goblet cell hyperplasia in Chinese NP patients and to characterize the signaling pathway underlying IL-17A-induced MUC5AC expression in vitro. Method We enrolled 25 NP patients and 22 normal controls and examined the expression of IL-17A, MUC5AC and act1 in polyp tissues by immunohistochemical (IHC) staining, quantitative polymerase chain reaction (qPCR) and western blot. Moreover, by using an in vitro culture system of polyp epithelial cells (PECs), IL-17A-induced gene expression was screened in cultured PECs by DNA microarray. The expression of IL-17RA, IL-17RC, act1 and MUC5AC and the activation of the MAPK pathway (ERK, p38 and JNK), were further examined in cultured PECs and NCI-H292 cells by qPCR and western blotting, respectively. Results We found that increased IL-17A production was significantly correlated with MUC5AC and act1 expression and goblet cell hyperplasia in polyp tissues (p<0.05). IL-17A significantly stimulated the expression of IL-17RA, IL-17RC, act1 and MUC5AC, and the activation of the MAPK pathway in cultured PECs and NCI-H292 cells (p<0.05). In addition, IL-17RA, IL-17RC and act1 siRNA significantly blocked IL-17A-induced MUC5AC production in vitro (p<0.05). Conclusion Our results suggest that IL-17A plays a crucial role in stimulating the production of MUC5AC and goblet cell hyperplasia through the act1-mediated signaling pathway and may suggest a promising strategy for the management of Th17-dominant NP patients.
    PLoS ONE 06/2014; 9(6):e98915. DOI:10.1371/journal.pone.0098915 · 3.23 Impact Factor
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    • "In most target cells, IL-17A signaling activates the MAPK and NF-κB pathways through IL-17RA and increases the expression of inflammatory cytokines [16]. Act1 has been identified as an essential adaptor molecule in IL-17 signaling [19]. In addition, the results of a microarray screen suggested the involvement of the CCAAT/enhancer binding protein transcription factors C/EBPβ and C/EBPδ in the IL-17A-induced signaling cascade [20], while another report showed that the PI3K pathway is involved in IL-17A signaling, mainly in an Act1-independent manner [21], but the underlying mechanisms remain largely unclear. "
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    ABSTRACT: Our previous data suggested that IL-17A contributes to the inhibition of Th1 cell function in the gut. However, the underlying mechanisms remain unclear. Here we demonstrate that IL-17A signaling in colonic epithelial cells (CECs) increases TNF-α-induced PI3K-AKT and ERK phosphorylation and inhibits TNF-α induced expression of IL-12P35 and of a Th1 cell chemokine, CXCL11 at mRNA level. In a co-culture system using HT-29 cells and PBMCs, IL-17A inhibited TNF-ãinduced IL-12P35 expression by HT-29 cells and led to decreased expression of IFN-γ and T-bet by PBMCs. Finally, adoptive transfer of CECs from mice with Crohn's Disease (CD) led to an enhanced Th1 cell response and exacerbated colitis in CD mouse recipients. The pathogenic effect of CECs derived from CD mice was reversed by co-administration of recombinant IL-17A. Our data demonstrate a new IL-17A-mediated regulatory mechanism in CD. A better understanding of this pathway might shed new light on the pathogenesis of CD.
    PLoS ONE 02/2014; 9(2):e89714. DOI:10.1371/journal.pone.0089714 · 3.23 Impact Factor
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