IRF5 gene, MANY conditions, crohn's, UC, SLE, Behcet's, etc

[Mike Bartolatz]

IRF5 for disorders About GeneDecksing

OMIM: 607218 disorders: 612245 612251
UniProtKB/Swiss-Prot: IRF5_HUMAN, Q13568

Genetic variations in IRF5 are associated with susceptibility to inflammatory bowel disease type 14 (IBD14)
[MIM:612245]. IBD14 is a chronic, relapsing inflammation of the gastrointestinal tract with a complex etiology. It is
subdivided into Crohn disease and ulcerative colitis phenotypes. Crohn disease may affect any part of the
gastrointestinal tract from the mouth to the anus, but most frequently it involves the terminal ileum and colon. Bowel
inflammation is transmural and discontinuous; it may contain granulomas or be associated with intestinal or perianal
fistulas. In contrast, in ulcerative colitis, the inflammation is continuous and limited to rectal and colonic mucosal
layers; fistulas and granulomas are not observed. Both diseases include extraintestinal inflammation of the skin,
eyes, or joints
Genetic variations in IRF5 are associated with susceptibility to systemic lupus erythematosus type 10 (SLEB10)
[MIM:612251]. Systemic lupus erythematosus (SLE) is a chronic, inflammatory and often febrile multisystemic disorder
of connective tissue. It affects principally the skin, joints, kidneys and serosal membranes. It is thought to
represent a failure of the regulatory mechanisms of the autoimmune system
Genetic variations in IRF5 are associated with susceptibility to rheumatoid arthritis (RA) [MIM:180300].
Rheumatoid arthritis is a complex, multifactorial disorder. It is one of the most common autoimmune diseases and it is
characterized by inflammation of synovial tissue and joint destruction

10/37 Novoseek disease relationships for IRF5 gene (see all 37)
Disease -log (P-Val) Hits PubMed IDs for Articles with Shared Sentences (# sentences)
lupus erythematosus systemic 100.00 96 18668568 (7), 18063667 (6), 19043711 (5), 20080916 (4) (see all 38)
ra 28.20 41 18438842 (7), 18843785 (6), 17158136 (5), 17133578 (5) (see all 13)
sclerosis; systemic 15.58 15 19644887 (6), 19116937 (5), 19479858 (4)
subacute cutaneous lupus erythematosus 7.82 4 19758313 (4)
disease; inflammatory bowel 7.76 11 20127100 (4), 17881657 (4), 19778284 (1), 18285424 (1) (see all 5)
autoimmune disease 5.95 9 18063667 (2), 20007534 (1), 19778284 (1), 18824541 (1) (see all
behcet disease 4.05 3 19816589 (3)
autoimmunities 3.71 5 20007534 (1), 19103199 (1), 18285424 (1), 17166181 (1) (see all 5)
acute coronary syndrome 3.27 5 19778284 (5)
arteritis; giant cell 3.21 3 19918036 (3)
About this table

Human Gene Mutation Database (HGMD): IRF5
Genetic Association Database (GAD): IRF5
Human Genome Epidemiology (HuGE) Navigator: IRF5 (75 documents)



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[Mike Bartolatz]

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Performing your original search, IRF5 protein, in PubMed will retrieve 151 records.

PLoS Pathog. 2009 Jul;5(7):e1000500. Epub 2009 Jul 3.

NOD2, RIP2 and IRF5 play a critical role in the type I interferon response to Mycobacterium tuberculosis.
Pandey AK, Yang Y, Jiang Z, Fortune SM, Coulombe F, Behr MA, Fitzgerald KA, Sassetti CM, Kelliher MA.

Department of Molecular Genetics and Microbiology, University of Massachusetts Medical School, Worcester, MA, USA.

Abstract
While the recognition of microbial infection often occurs at the cell surface via Toll-like receptors, the cytosol of the cell is also under surveillance for microbial products that breach the cell membrane. An important outcome of cytosolic recognition is the induction of IFNalpha and IFNbeta, which are critical mediators of immunity against both bacteria and viruses. Like many intracellular pathogens, a significant fraction of the transcriptional response to Mycobacterium tuberculosis infection depends on these type I interferons, but the recognition pathways responsible remain elusive. In this work, we demonstrate that intraphagosomal M. tuberculosis stimulates the cytosolic Nod2 pathway that responds to bacterial peptidoglycan, and this event requires membrane damage that is actively inflicted by the bacterium. Unexpectedly, this recognition triggers the expression of type I interferons in a Tbk1- and Irf5-dependent manner. This response is only partially impaired by the loss of Irf3 and therefore, differs fundamentally from those stimulated by bacterial DNA, which depend entirely on this transcription factor. This difference appears to result from the unusual peptidoglycan produced by mycobacteria, which we show is a uniquely potent agonist of the Nod2/Rip2/Irf5 pathway. Thus, the Nod2 system is specialized to recognize bacteria that actively perturb host membranes and is remarkably sensitive to mycobacteria, perhaps reflecting the strong evolutionary pressure exerted by these pathogens on the mammalian immune system.

PMID: 19578435 [PubMed - indexed for MEDLINE]PMCID: PMC2698121Free PMC Article



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Figure 1Live, intracellular Mycobacterium tuberculosis stimulates Rip2 polyubiquitination.A. Live, but not heat killed Mtb (Rv) stimulates Rip2 polyubiquitination. Bone marrow-derived macrophages (BMDM) were infected with live virulent (Rv) or heat killed (HK-Rv) strains of M. tuberculosis (strain H37Rv) for the indicated times. Polyubiquitinated Rip2 protein was detected by immunoprecipitating the cel...NOD2, RIP2 and IRF5 Play a Critical Role in the Type I Interferon Response to Mycobacterium tuberculosisPLoS Pathog. 2009 July;5(7):e1000500.Figure 2Rip2 polyubiquitination upon Mtb infection requires ESX-1.The murine RAW 264.7 macrophage cell line was left uninfected (UI), infected with Mtb H37Rv (Rv), with ESX1 mutant strains of Mtb (ΔESX1, ΔespA), with a complemented ΔespA-C strain, with the attenuated vaccine strain Mycobacterium bovis BCG or with the unrelated attenuated mutants Tn::rv1410 and ΔbioF. Cell lysates were immunoprecipitate...NOD2, RIP2 and IRF5 Play a Critical Role in the Type I Interferon Response to Mycobacterium tuberculosisPLoS Pathog. 2009 July;5(7):e1000500.Figure 3Membrane damage allows Nod2-mediated recognition of ESX1 mutants.A. The mouse RAW 264.7 macrophage cell line was was treated with ATP (5 mM) or SLO (5 µg/ml) for 15 minutes before infection with virulent wild type (Rv) or ESX1 mutant (ΔespA) strains of Mtb. After one hour, cell lysates were immunoprecipitated with a Rip2 antibody followed by immunoblotting with an an...NOD2, RIP2 and IRF5 Play a Critical Role in the Type I Interferon Response to Mycobacterium tuberculosisPLoS Pathog. 2009 July;5(7):e1000500.Figure 4Type I Interferon production upon Mtb infection is reduced in Rip2- and Nod2-deficient macrophages.A, B, E, and F. BMDM derived from wt, rip2−/− and nod2−/− mice were infected with Mtb (MOI 10) for 4 h. RNA was harvested and IFNα, IFNβ, RANTES and TNFα mRNA levels were quantified using real time PCR. Gene expression is reported as copy number per 1,000 copies of β-actin. Samples were assayed in triplicate; error...NOD2, RIP2 and IRF5 Play a Critical Role in the Type I Interferon Response to Mycobacterium tuberculosisPLoS Pathog. 2009 July;5(7):e1000500.Figure 5Multiple cytosolic pathways lead to IFNβ induction.A. BMDM derived from wt, rip2−/− and nod2−/− mice were infected with virulent Mtb H37Rv (Rv) or with an ESX1 mutant (ΔESX1) at an MOI of 10 for 4 h. RNA was harvested, and IFNβ mRNA levels were quantified using real time PCR. Gene expression of IFNβ is reported as copy number per 1,000 copies of β-actin. Samples we...NOD2, RIP2 and IRF5 Play a Critical Role in the Type I Interferon Response to Mycobacterium tuberculosisPLoS Pathog. 2009 July;5(7):e1000500.Figure 6Nod2 stimulation is sufficient for type I IFN induction.A and B. N-Glycolyl MDP is more potent than the more common N-Acetylated derivative. The macrophage cell line RAW 264.7 was treated with the indicated concentrations of N-Glycolyl-MDP or N-Acetyl-MDP for 4 h. RNA was harvested, and IFNβ and RANTES mRNA levels were quantified using real time PCR. Gene ex...NOD2, RIP2 and IRF5 Play a Critical Role in the Type I Interferon Response to Mycobacterium tuberculosisPLoS Pathog. 2009 July;5(7):e1000500.Figure 7Mtb-induced type I IFN response is Tbk1-dependent and mediated through both Irf3 and Irf5.A. M. tuberculosis-induced type I IFN response is Tbk1-dependent and only partially mediated through Irf3. BMDM derived from wt, irf3−/− and tbk1−/−tnfr1−/− mice and littermate controls were infected with virulent Mtb H37Rv (Rv) at an MOI of 10 for 4 h. RNA was harvested and IFNβ mRNA level was quantified using real time PCR. Gene expres...NOD2, RIP2 and IRF5 Play a Critical Role in the Type I Interferon Response to Mycobacterium tuberculosisPLoS Pathog. 2009 July;5(7):e1000500.Figure 8The N-Glycolyl-MDP-induced type I IFN response is Irf5-dependent and Irf3 independent.BMDM derived from irf3−/− and irf5−/− mice and their littermate controls were left untreated or treated for 6 hours with 10 µg/ml of N-Glycolyl-MDP. RNA was harvested, and IFNβ mRNA levels were quantified using real time PCR. IFNβ mRNA levels are reported as copy number per 1,000 copies of β-actin. Samples were as...NOD2, RIP2 and IRF5 Play a Critical Role in the Type I Interferon Response to Mycobacterium tuberculosisPLoS Pathog. 2009 July;5(7):e1000500.Publication Types, MeSH Terms, Substances, Grant SupportPublication Types: Research Support, N.I.H., ExtramuralMeSH Terms:Acetylmuramyl-Alanyl-Isoglutamine/metabolismAnimalsBacterial Proteins/geneticsCell LineInterferon Regulatory Factor-3/immunologyInterferon Regulatory Factor-3/metabolismInterferon Regulatory Factors/immunology*Interferon Regulatory Factors/metabolismInterferon Type I/biosynthesisInterferon Type I/immunology*Interferon Type I/metabolismMacrophages/immunologyMacrophages/metabolismMiceMice, Inbred C57BLMutationMycobacterium tuberculosis/geneticsMycobacterium tuberculosis/immunology*Nod2 Signaling Adaptor Protein/immunology*Nod2 Signaling Adaptor Protein/metabolismProtein-Serine-Threonine Kinases/immunologyProtein-Serine-Threonine Kinases/metabolismReceptor-Interacting Protein Serine-Threonine Kinases/immunology*Receptor-Interacting Protein Serine-Threonine Kinases/metabolismTuberculosis/immunology*Tuberculosis/metabolismTuberculosis/microbiologyUbiquitin/immunologyUbiquitin/metabolismSubstances:Bacterial ProteinsCard15 protein, mouseInterferon Regulatory Factor-3Interferon Regulatory FactorsInterferon Type IIrf3 protein, mouseIrf5 protein, mouseNod2 Signaling Adaptor ProteinUbiquitinAcetylmuramyl-Alanyl-IsoglutamineRipk2 protein, mouseTbk1 protein, mouseProtein-Serine-Threonine KinasesReceptor-Interacting Protein Serine-Threonine KinasesGrant Support:R01 AI064282/AI/NIAID NIH HHS/United StatesR01 AI067497/AI/NIAID NIH HHS/United StatesR01 AI075118/AI/NIAID NIH HHS/United States
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[Mike Bartolatz]

Blood, 3 June 2010, Vol. 115, No. 22, pp. 4421-4430.
Prepublished online as a Blood First Edition Paper on March 17, 2010; DOI 10.1182/blood-2010-01-263020.

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IMMUNOBIOLOGY

IRF5 is required for late-phase TNF secretion by human dendritic cells
Thomas Krausgruber1,*, David Saliba1,*, Grigory Ryzhakov1, Alessandra Lanfrancotti1, Katrina Blazek1, and Irina A. Udalova1
1 Kennedy Institute of Rheumatology Division, Faculty of Medicine, Imperial College of Science, Technology and Medicine, London, United Kingdom


Spatially and temporally controlled expression of inflammatory mediators is critical for an appropriate immune response. In this study, we define the role for interferon regulatory factor 5 (IRF5) in secretion of tumor necrosis factor (TNF) by human dendritic cells (DCs). We demonstrate that DCs but not macrophages have high levels of IRF5 protein, and that IRF5 is responsible for the late-phase expression of TNF, which is absent in macrophages. Sustained TNF secretion is essential for robust T-cell activation by DCs. Systematic bioinformatic and biochemical analyses of the TNF gene locus map 2 sites of IRF5 recruitment: 5' upstream and 3' downstream of the TNF gene. Remarkably, while IRF5 can directly bind to DNA in the upstream region, its recruitment to the downstream region depends on the protein-protein interactions with NF-B RelA. This study provides new insights into diverse molecular mechanisms employed by IRF5 to regulate gene expression and implicates RelA-IRF5 interactions as a putative target for cell-specific modulation of TNF expression.


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