1 6009 126 THE ANTI-INFLAMMATORY MEDIATOR, VASOACTIVE INTESTINAL PEPTIDE, MODULATES THE DIFFERENTIATION AND FUNCTION OF TH SUBSETS IN RHEUMATOID ARTHRITIS. GENETIC BACKGROUND, EPIGENETIC MODIFICATIONS, AND ENVIRONMENTAL FACTORS TRIGGER AUTOIMMUNE RESPONSE IN RHEUMATOID ARTHRITIS (RA). SEVERAL PATHOGENIC INFECTIONS HAVE BEEN RELATED TO THE ONSET OF RA AND MAY CAUSE AN INADEQUATE IMMUNOLOGICAL TOLERANCE TOWARDS CRITICAL SELF-ANTIGENS LEADING TO CHRONIC JOINT INFLAMMATION AND AN IMBALANCE BETWEEN DIFFERENT T HELPER (TH) SUBSETS. VASOACTIVE INTESTINAL PEPTIDE (VIP) IS A MEDIATOR THAT MODULATES ALL THE STAGES COMPRISED BETWEEN THE ARRIVAL OF PATHOGENS AND TH CELL DIFFERENTIATION IN RA THROUGH ITS KNOWN ANTI-INFLAMMATORY AND IMMUNOMODULATORY ACTIONS. THIS "NEUROIMMUNOPEPTIDE" MODULATES THE PATHOGENIC ACTIVITY OF DIVERSE CELL SUBPOPULATIONS INVOLVED IN RA AS LYMPHOCYTES, FIBROBLAST-LIKE SYNOVIOCYTES (FLS), OR MACROPHAGES. IN ADDITION, VIP DECREASES THE EXPRESSION OF PATTERN RECOGNITION RECEPTOR (PRR) SUCH AS TOLL-LIKE RECEPTORS (TLRS) IN FLS FROM RA PATIENTS. THESE RECEPTORS ACT AS SENSORS OF PATHOGEN-ASSOCIATED MOLECULAR PATTERN (PAMP) AND DAMAGE-ASSOCIATED MOLECULAR PATTERN (DAMP) CONNECTING THE INNATE AND ADAPTIVE IMMUNE SYSTEM. MOREOVER, VIP MODULATES THE IMBALANCE BETWEEN TH SUBSETS IN RA, DECREASING PATHOGENIC TH1 AND TH17 SUBSETS AND FAVORING TH2 OR TREG PROFILE DURING THE DIFFERENTIATION/POLARIZATION OF NAIVE OR MEMORY TH CELLS. FINALLY, VIP REGULATES THE PLASTICITY BETWEEN THESES SUBSETS. IN THIS REVIEW, WE PROVIDE AN OVERVIEW OF VIP EFFECTS ON THE AFOREMENTIONED FEATURES OF RA PATHOLOGY. 2018 2 4535 32 MULTIPLE ROLES OF TOLL-LIKE RECEPTOR 4 IN COLORECTAL CANCER. TOLL-LIKE RECEPTOR (TLR) SIGNALING HAS BEEN IMPLICATED IN THE INFLAMMATORY RESPONSES IN INTESTINAL EPITHELIAL CELLS (IECS). SUCH INFLAMMATORY SIGNALS MEDIATE COMPLEX INTERACTIONS BETWEEN COMMENSAL BACTERIA AND TLRS AND ARE REQUIRED FOR IEC PROLIFERATION, IMMUNE RESPONSE, REPAIR, AND HOMEOSTASIS. THE UPREGULATION OF CERTAIN TLRS IN COLORECTAL CANCER (CRC) TISSUES SUGGESTS THAT TLRS MAY PLAY AN ESSENTIAL ROLE IN THE PROGNOSIS OF CHRONIC AND INFLAMMATORY DISEASES THAT ULTIMATELY CULMINATE IN CRC. HERE, WE PROVIDE A COMPREHENSIVE REVIEW OF THE LITERATURE ON THE INVOLVEMENT OF THE TLR PATHWAY IN THE INITIATION, PROGRESSION, AND METASTASIS OF CRC, AS WELL AS INHERITED GENETIC VARIATION AND EPIGENETIC REGULATION. THE DIFFERENTIAL EXPRESSION OF TLRS IN EPITHELIAL CELLS HAS ALSO BEEN DISCUSSED. IN PARTICULAR, WE EMPHASIZE THE PHYSIOLOGICAL ROLE OF TLR4 IN CRC DEVELOPMENT AND PATHOGENESIS, AND PROPOSE NOVEL AND PROMISING APPROACHES FOR CRC THERAPEUTICS WITH THE AID OF TLR LIGANDS. 2014 3 6476 33 TOLL-LIKE RECEPTORS, INFECTIONS, AND RHEUMATOID ARTHRITIS. TOLL-LIKE RECEPTORS (TLR) THAT BELONG TO THE GROUP OF PROTEIN RECOGNITION RECEPTOR (PPR) PROVIDE AN INNATE IMMUNE RESPONSE FOLLOWING THE SENSING OF CONSERVED PATHOGEN-ASSOCIATED MICROBIAL PATTERNS (PAMPS) AND CHANGES IN DANGER-ASSOCIATED MOLECULAR PATTERNS (DAMPS) THAT ARE GENERATED AS A CONSEQUENCE OF CELLULAR INJURY. ANALYSIS OF THE TLR PATHWAY HAS MOREOVER OFFERED NEW INSIGHTS INTO THE PATHOGENESIS OF RHEUMATOID ARTHRITIS (RA). INDEED, A DYSFUNCTIONAL TLR-MEDIATED RESPONSE CHARACTERIZES RA PATIENTS AND PARTICIPATES IN ESTABLISHMENT OF A CHRONIC INFLAMMATORY STATE. SUCH AN INAPPROPRIATE TLR RESPONSE HAS BEEN ATTRIBUTED (I) TO THE REPORT OF IMPORTANT ALTERATIONS IN THE MICROBIOTA AND ABNORMAL RESPONSES TO INFECTIOUS AGENTS AS PART OF RA; (II) TO THE ABNORMAL PRESENCE OF TLR-LIGANDS IN THE SERUM AND SYNOVIAL FLUID OF RA PATIENTS; (III) TO THE OVEREXPRESSION OF TLR MOLECULES; (IV) TO THE PRODUCTION OF A LARGE PANEL OF PRO-INFLAMMATORY CYTOKINES DOWNSTREAM OF THE TLR PATHWAY; AND (V) TO GENETIC VARIANTS AND EPIGENETIC FACTORS IN SUSCEPTIBLE RA PATIENTS PROMOTING A HYPER TLR RESPONSE. AS A CONSEQUENCE, THE DEVELOPMENT OF PROMISING THERAPEUTIC STRATEGIES TARGETING TLRS FOR THE TREATMENT AND PREVENTION OF RA IS EMERGING. 2020 4 5507 30 RHEUMATOID ARTHRITIS PROGRESSION MEDIATED BY ACTIVATED SYNOVIAL FIBROBLASTS. RHEUMATOID ARTHRITIS (RA) IS A CHRONIC INFLAMMATORY DISEASE CHARACTERIZED BY SYNOVIAL HYPERPLASIA AND PROGRESSIVE JOINT DESTRUCTION. RHEUMATOID ARTHRITIS SYNOVIAL FIBROBLASTS (RASFS) ARE LEADING CELLS IN JOINT EROSION AND CONTRIBUTE ACTIVELY TO INFLAMMATION. RASFS SHOW AN ACTIVATED PHENOTYPE THAT IS INDEPENDENT OF THE INFLAMMATORY ENVIRONMENT AND REQUIRES THE COMBINATION OF SEVERAL FACTORS. ALTHOUGH NEW ASPECTS REGARDING RASF ACTIVATION VIA MATRIX DEGRADATION PRODUCTS, EPIGENETIC MODIFICATIONS, INFLAMMATORY FACTORS, TOLL-LIKE RECEPTOR (TLR) ACTIVATION AND OTHERS HAVE RECENTLY BEEN UNCOVERED, THE PRIMARY PATHOPHYSIOLOGICAL PROCESSES IN EARLY ARTHRITIS LEADING TO PERMANENT ACTIVATION ARE MOSTLY UNKNOWN. HERE, WE REVIEW NEW FINDINGS REGARDING RASF ACTIVATION AND THEIR ALTERED BEHAVIOR THAT CONTRIBUTE TO MATRIX DESTRUCTION AND INFLAMMATION AS WELL AS THEIR POTENTIAL TO SPREAD RA. 2010 5 4412 33 MOLECULAR AND CELLULAR BASIS OF RHEUMATOID JOINT DESTRUCTION. RHEUMATOID ARTHRITIS (RA) IS A CHRONIC INFLAMMATORY DISEASE ASSOCIATED WITH JOINT DESTRUCTION. SYNOVIAL FIBROBLASTS ARE KEY PLAYERS IN THIS PATHOLOGICAL PROCESS. THEY FAVORISE A PRO-INFLAMMATORY ENVIRONMENT IN THE SYNOVIAL TISSUE, INTERACT WITH THE IMMUNE SYSTEM AND REGULATE THE DIFFERENTIATION OF MONOCYTES INTO OSTEOCLASTS. SYNOVIAL HYPERPLASIA IS ANOTHER CHARACTERISTIC OF RA, REFLECTING NOT ONLY AN IMBALANCE BETWEEN PROLIFERATION AND APOPTOSIS, BUT ALSO THE MIGRATION OF CELLS INTO THE SYNOVIAL TISSUE. GENE TRANSFER EXPERIMENTS HAVE BEEN USED AS IMPORTANT TOOLS FOR THE UNDERSTANDING OF MOLECULAR AND CELLULAR CHANGES THAT CHARACTERIZE THE ACTIVATED RA SYNOVIAL FIBROBLASTS. ACTIVATED SYNOVIAL FIBROBLASTS CAN INVADE CARTILAGE AND BONE. SYNOVIAL ACTIVATION IS DRIVEN BY CYTOKINES, SUCH AS TNFALPHA AND IL-1, AS WELL AS IL-15, 16, 17, 18, 22, 23, BUT ALSO BY CYTOKINE-INDEPENDENT MECHANISMS THAT INVOLVE THE INNATE IMMUNE SYSTEM (I.E. TLRS), A UNIQUE COMMUNICATION NETWORK OF MICROPARTICLES AND EPIGENETIC CHANGES (E.G. L1 RETROELEMENTS). 2006 6 3737 42 INNATE IMMUNITY, EPIGENETICS AND AUTOIMMUNITY IN RHEUMATOID ARTHRITIS. RHEUMATOID ARTHRITIS (RA) IS A CHRONIC INFLAMMATORY AUTOIMMUNE DISEASE CHARACTERIZED BY THE PROGRESSIVE AND IRREVERSIBLE DESTRUCTION OF JOINTS. RA REMAINS AN INCURABLE CONDITION, ALTHOUGH A NEW CLASS OF DRUGS, BIOLOGICALS, HAVE MADE A MAJOR BREAKTHROUGH IN TARGETING AND/OR ELIMINATING THE IMMUNE CELLS, INCLUDING T CELLS, B CELLS AND MONOCYTES/MACROPHAGES FROM THE JOINTS. THAT WE CANNOT (YET?) CURE THE DISEASE IS MOST LIKELY DUE TO THE LACK OF THERAPEUTIC TARGETING THE ENDOGENOUSLY ACTIVATED RA SYNOVIAL FIBROBLASTS (RASF). MOST INTERESTINGLY, RASF EXPRESS TOLL-LIKE RECEPTORS (TLRS) 1-6 RENDERING THEM PRONE TO ACTIVATION BY EXOGENOUS AND ENDOGENOUS TLR LIGANDS AND RESULTING IN THE PRODUCTION OF NUMEROUS POWERFUL CHEMOKINES AND CYTOKINES. THESE FACTORS ARE RESPONSIBLE FOR THE REPOPULATION OF IMMUNE CELLS IN THE JOINTS AFTER CEASING CELL DEPLETING THERAPIES. TO CHARACTERIZE THE MOLECULAR MECHANISMS OF SYNOVIAL ACTIVATION, A NEW APPROACH STUDYING THE EPIGENETIC CHARACTERISTICS OF RASF HAS BEEN RECENTLY UNDERTAKEN. THEREBY, THE PATTERN OF HISTONE ACETYLATION, DNA METHYLATION AND GENE EXPRESSION REGULATING MICRORNA ARE BEING EXPLORED. SINCE AUTO-ANTIBODIES HAVE THE MOST PREDICTIVE AND DIAGNOSTIC VALUE FOR RA, IT IS CHALLENGING TO STUDY MORE COMPREHENSIVELY THE CONTRIBUTION OF AUTO-ANTIBODIES TO THE DISEASE. A NEW SCREENING TECHNIQUE, SEROLOGICAL ANALYSIS OF RECOMBINANT HUMAN CDNA EXPRESSION LIBRARY (SEREX), ADAPTED FROM CANCER RESEARCH ALLOWED FOR THE IDENTIFICATION OF NOVEL AUTO-ANTIBODIES IN RA, INCLUDING ANTI-SERPIN E2 AUTO-ANTIBODIES. THE SERPIN E2 AUTO-ANTIBODIES WERE FOUND TO INHIBIT THE ACTIVITY OF SERPIN E2 AND HAVE POTENTIALLY A FUNCTIONAL ROLE IN THE DISEASE. THE RECENT FINDINGS IN THE FIELD OF INNATE IMMUNITY, EPIGENETICS AND AUTOIMMUNITY RELATED TO THE PATHOGENESIS OF RA ARE IN THE SCOPE OF THIS REVIEW. 2009 7 5301 26 PROTEIN PHOSPHATASE 2A CATALYTIC SUBUNIT ALPHA PLAYS A MYD88-DEPENDENT, CENTRAL ROLE IN THE GENE-SPECIFIC REGULATION OF ENDOTOXIN TOLERANCE. MYD88, THE INTRACELLULAR ADAPTOR OF MOST TLRS, MEDIATES EITHER PROINFLAMMATORY OR IMMUNOSUPPRESSIVE SIGNALING THAT CONTRIBUTES TO CHRONIC INFLAMMATION-ASSOCIATED DISEASES. ALTHOUGH GENE-SPECIFIC CHROMATIN MODIFICATIONS REGULATE INFLAMMATION, THE ROLE OF MYD88 SIGNALING IN ESTABLISHING SUCH EPIGENETIC LANDSCAPES UNDER DIFFERENT INFLAMMATORY STATES REMAINS ELUSIVE. USING QUANTITATIVE PROTEOMICS TO ENUMERATE THE INFLAMMATION-PHENOTYPIC CONSTITUENTS OF THE MYD88 INTERACTOME, WE FOUND THAT IN ENDOTOXIN-TOLERANT MACROPHAGES, PROTEIN PHOSPHATASE 2A CATALYTIC SUBUNIT ALPHA (PP2AC) ENHANCES ITS ASSOCIATION WITH MYD88 AND IS CONSTITUTIVELY ACTIVATED. KNOCKDOWN OF PP2AC PREVENTS SUPPRESSION OF PROINFLAMMATORY GENES AND RESISTANCE TO APOPTOSIS. THROUGH SITE-SPECIFIC DEPHOSPHORYLATION, CONSTITUTIVELY ACTIVE PP2AC DISRUPTS THE SIGNAL-PROMOTING TLR4-MYD88 COMPLEX AND BROADLY SUPPRESSES THE ACTIVITIES OF MULTIPLE PROINFLAMMATORY/PROAPOPTOTIC PATHWAYS AS WELL, SHIFTING PROINFLAMMATORY MYD88 SIGNALING TO A PROSURVIVAL MODE. CONSTITUTIVELY ACTIVE PP2AC TRANSLOCATED WITH MYD88 INTO THE NUCLEI OF TOLERANT MACROPHAGES ESTABLISHES THE IMMUNOSUPPRESSIVE PATTERN OF CHROMATIN MODIFICATIONS AND REPRESSES CHROMATIN REMODELING TO SELECTIVELY SILENCE PROINFLAMMATORY GENES, COORDINATING THE MYD88-DEPENDENT INFLAMMATION CONTROL AT BOTH SIGNALING AND EPIGENETIC LEVELS UNDER ENDOTOXIN-TOLERANT CONDITIONS. 2013 8 1173 39 CONTRIBUTION OF TLR SIGNALING TO THE PATHOGENESIS OF COLITIS-ASSOCIATED CANCER IN INFLAMMATORY BOWEL DISEASE. IN THE INTESTINE A BALANCE BETWEEN PROINFLAMMATORY AND REPAIR SIGNALS OF THE IMMUNE SYSTEM IS ESSENTIAL FOR THE MAINTENANCE OF INTESTINAL HOMEOSTASIS. THE INNATE IMMUNITY ENSURES A PRIMARY HOST RESPONSE TO MICROBIAL INVASION, WHICH INDUCES AN INFLAMMATORY PROCESS TO LOCALIZE THE INFECTION AND PREVENT SYSTEMIC DISSEMINATION OF PATHOGENS. THE KEY ELEMENTS OF THIS PROCESS ARE THE GERMLINE ENCODED PATTERN RECOGNITION RECEPTORS INCLUDING TOLL-LIKE RECEPTORS (TLRS). IF PATHOGENS CANNOT BE ELIMINATED, THEY MAY ELICIT CHRONIC INFLAMMATION, WHICH MAY BE PARTLY MEDIATED VIA TLRS. ADDITIONALLY, CHRONIC INFLAMMATION HAS LONG BEEN SUGGESTED TO TRIGGER TISSUE TUMOROUS TRANSFORMATION. INFLAMMATION, THE SEVENTH HALLMARK OF CANCER, MAY AFFECT ALL PHASES OF TUMOR DEVELOPMENT, AND EVADE THE IMMUNE SYSTEM. INFLAMMATION ACTS AS A CELLULAR STRESSOR AND MAY TRIGGER DNA DAMAGE OR GENETIC INSTABILITY. FURTHERMORE, CHRONIC INFLAMMATION CAN PROVOKE GENETIC MUTATIONS AND EPIGENETIC MECHANISMS THAT PROMOTE MALIGNANT CELL TRANSFORMATION. COLORECTAL CANCERS IN INFLAMMATORY BOWEL DISEASE PATIENTS ARE CONSIDERED TYPICAL EXAMPLES OF INFLAMMATION-RELATED CANCERS. ALTHOUGH DATA REGARDING THE ROLE OF TLRS IN THE PATHOMECHANISM OF CANCER-ASSOCIATED COLITIS ARE RATHER CONFLICTING, FUNCTIONALLY THESE MOLECULES CAN BE CLASSIFIED AS "LARGELY ANTITUMORIGENIC" AND "LARGELY PRO-TUMORIGENIC" WITH THE CAVEAT THAT THE UNDERLYING SIGNALING PATHWAYS ARE MAINLY CONTEXT (I.E., ORGAN-, TISSUE-, CELL-) AND LIGAND-DEPENDENT. 2014 9 3789 34 INTERLEUKIN 17 CONTRIBUTES TO THE CHRONICITY OF INFLAMMATORY DISEASES SUCH AS RHEUMATOID ARTHRITIS. RHEUMATOID ARTHRITIS (RA) IS A CHRONIC INFLAMMATORY DISEASE LEADING TO JOINT DESTRUCTION AND BONE RESORPTION. THE PROINFLAMMATORY CYTOKINE INTERLEUKIN 17 (IL-17), PRIMARILY PRODUCED BY TH17 CELLS, HAS BEEN SHOWN TO BE INVOLVED IN ALL STAGES OF THE DISEASE AND TO BE AN IMPORTANT CONTRIBUTOR OF RA CHRONICITY. THREE MAJOR PROCESSES DRIVE THE IL-17-MEDIATED CHRONICITY. SEVERAL EPIGENETIC EVENTS, ENHANCED IN RA PATIENTS, LEAD TO THE INCREASED PRODUCTION OF IL-17 BY TH17 CELLS. IL-17 THEN INDUCES THE PRODUCTION OF SEVERAL INFLAMMATORY MEDIATORS IN THE DISEASED SYNOVIUM, WHICH ARE FURTHER SYNERGISTICALLY ENHANCED VIA COMBINATIONS OF IL-17 WITH OTHER CYTOKINES. IL-17 ALSO PROMOTES THE SURVIVAL OF BOTH THE SYNOVIOCYTES AND INFLAMMATORY CELLS AND PROMOTES THE MATURATION OF THESE IMMUNE CELLS. THIS LEADS TO AN INCREASED NUMBER OF SYNOVIOCYTES AND INFLAMMATORY CELLS IN THE SYNOVIAL FLUID AND IN THE SYNOVIUM LEADING TO THE HYPERPLASIA AND EXACERBATED INFLAMMATION OBSERVED IN JOINTS OF RA PATIENTS. FURTHERMORE, THESE IL-17-DRIVEN EVENTS INITIATE SEVERAL FEEDBACK-LOOP MECHANISMS LEADING TO INCREASED EXPANSION OF TH17 CELLS AND THEREBY INCREASED PRODUCTION OF IL-17. IN THIS REVIEW, WE AIM TO DEPICT A COMPLETE PICTURE OF THE IL-17-DRIVEN VICIOUS CIRCLE LEADING TO RA CHRONICITY AND TO PINPOINT THE KEY ASPECTS THAT REQUIRE FURTHER EXPLORATION. 2014 10 6741 34 WHERE TO STAND WITH STROMAL CELLS AND CHRONIC SYNOVITIS IN RHEUMATOID ARTHRITIS? THE SYNOVIUM EXERCISES ITS MAIN FUNCTION IN JOINT HOMEOSTASIS THROUGH THE SECRETION OF FACTORS (SUCH AS LUBRICIN AND HYALURONIC ACID) THAT ARE CRITICAL FOR THE JOINT LUBRICATION AND FUNCTION. THE MAIN SYNOVIUM CELL COMPONENTS ARE FIBROBLAST-LIKE SYNOVIOCYTES, MESENCHYMAL STROMAL/STEM CELLS AND MACROPHAGE-LIKE SYNOVIAL CELLS. IN THE SYNOVIUM, CELLS OF MESENCHYMAL ORIGIN MODULATE LOCAL INFLAMMATION AND FIBROSIS, AND INTERACT WITH DIFFERENT FIBROBLAST SUBTYPES AND WITH RESIDENT MACROPHAGES. IN PATHOLOGIC CONDITIONS, SUCH AS RHEUMATOID ARTHRITIS, FIBROBLAST-LIKE SYNOVIOCYTES PROLIFERATE ABNORMALLY, RECRUIT MESENCHYMAL STEM CELLS FROM SUBCHONDRAL BONE MARROW, AND INFLUENCE IMMUNE CELL ACTIVITY THROUGH EPIGENETIC AND METABOLIC ADAPTATIONS. THE RESULTING SYNOVIAL HYPERPLASIA LEADS TO SECONDARY CARTILAGE DESTRUCTION, JOINT SWELLING, AND PAIN. IN THE PRESENT REVIEW, WE SUMMARIZE RECENT FINDINGS ON THE MOLECULAR SIGNATURE AND THE ROLES OF STROMAL CELLS DURING SYNOVIAL PANNUS FORMATION AND RHEUMATOID ARTHRITIS PROGRESSION. 2019 11 6470 26 TLR7 AND TLR8 EXPRESSION INCREASES TUMOR CELL PROLIFERATION AND PROMOTES CHEMORESISTANCE IN HUMAN PANCREATIC CANCER. CHRONIC INFLAMMATION AS AN IMPORTANT EPIGENETIC AND ENVIRONMENTAL FACTOR FOR PUTATIVE TUMORIGENESIS AND TUMOR PROGRESSION MAY BE ASSOCIATED WITH SPECIFIC ACTIVATION OF TOLL-LIKE RECEPTORS (TLR). RECENTLY, CARCINOGENESIS HAS BEEN SUGGESTED TO BE DEPENDENT ON TLR7 SIGNALING. IN THE PRESENT STUDY, WE DETERMINED THE ROLE OF BOTH TLR7 AND TLR8 EXPRESSION AND SIGNALING IN TUMOR CELL PROLIFERATION AND CHEMORESISTANCE IN PANCREATIC CANCER. EXPRESSION OF TLR7/TLR8 IN UICC STAGE I-IV PANCREATIC CANCER, CHRONIC PANCREATITIS, NORMAL PANCREATIC TISSUE AND HUMAN PANCREATIC (PANC1) CANCER CELL LINE WAS EXAMINED. FOR IN VITRO/IN VIVO STUDIES TLR7/TLR8 OVEREXPRESSING PANC1 CELL LINES WERE GENERATED AND ANALYZED FOR EFFECTS OF (UN-)STIMULATED TLR EXPRESSION ON TUMOR CELL PROLIFERATION AND CHEMORESISTANCE. TLR EXPRESSION WAS INCREASED IN PANCREATIC CANCER, WITH STAGE-DEPENDENT UPREGULATION IN ADVANCED TUMORS, COMPARED TO EARLIER STAGES AND CHRONIC PANCREATITIS. STIMULATION OF TLR7/TLR8 OVEREXPRESSING PANC1 CELLS RESULTED IN ELEVATED NF-KAPPAB AND COX-2 EXPRESSION, INCREASED CANCER CELL PROLIFERATION AND REDUCED CHEMOSENSITIVITY. MORE IMPORTANTLY, TLR7/TLR8 EXPRESSION INCREASED TUMOR GROWTH IN VIVO. OUR DATA DEMONSTRATE A STAGE-DEPENDENT UPREGULATION OF BOTH TLR7 AND TLR8 EXPRESSION IN PANCREATIC CANCER. FUNCTIONAL ANALYSIS IN HUMAN PANCREATIC CANCER CELLS POINT TO A SIGNIFICANT ROLE OF BOTH TLRS IN CHRONIC INFLAMMATION-MEDIATED TLR7/TLR8 SIGNALING LEADING TO TUMOR CELL PROLIFERATION AND CHEMORESISTANCE. 2015 12 2221 26 EPIGENETIC MODIFICATIONS IN RHEUMATOID ARTHRITIS, A REVIEW. RHEUMATOID ARTHRITIS IS AN AUTOIMMUNE DISEASE CHARACTERIZED BY CHRONIC JOINT INFLAMMATION AND PROGRESSIVE DESTRUCTION OF CARTILAGE AND BONE WHICH LEADS TO ULTIMATELY LOSS OF FUNCTION AND PAIN. ACTIVATED SYNOVIAL FIBROBLASTS ARE KEY EFFECTOR CELLS IN THE PATHOGENESIS OF RHEUMATOID ARTHRITIS. IN THE RECENT YEARS, EPIGENETIC CHANGES INCLUDING DNA METHYLATION, HISTONE ACETYLATION AND OTHER HISTONE MODIFICATIONS WERE IDENTIFIED THAT ARE ASSOCIATED WITH AN INTRINSIC ACTIVATION AND THE AGGRESSIVE PHENOTYPE OF THESE CELLS. SO FAR, NO THERAPIES TARGETING RHEUMATOID ARTHRITIS SYNOVIAL FIBROBLASTS EXIST. THIS REVIEW COMPRISES RECENT RESEARCH EFFORTS THAT PROPOSE EPIGENETIC MECHANISMS BEHIND THE ACTIVATION OF RHEUMATOID ARTHRITIS SYNOVIAL FIBROBLASTS AND OTHER CELL TYPES. 2013 13 2384 27 EPIGENETIC REGULATOR UHRF1 ORCHESTRATES PROINFLAMMATORY GENE EXPRESSION IN RHEUMATOID ARTHRITIS IN A SUPPRESSIVE MANNER. RHEUMATOID ARTHRITIS (RA) IS CHARACTERIZED BY CHRONIC SYNOVIAL INFLAMMATION WITH ABERRANT EPIGENETIC ALTERATIONS, EVENTUALLY LEADING TO JOINT DESTRUCTION. HOWEVER, THE EPIGENETIC REGULATORY MECHANISMS UNDERLYING RA PATHOGENESIS REMAIN LARGELY UNKNOWN. HERE, WE SHOWED THAT UBIQUITIN-LIKE CONTAINING PHD AND RING FINGER DOMAINS 1 (UHRF1) IS A CENTRAL EPIGENETIC REGULATOR THAT ORCHESTRATES MULTIPLE PATHOGENESES IN RA IN A SUPPRESSIVE MANNER. UHRF1 EXPRESSION WAS REMARKABLY UPREGULATED IN SYNOVIAL FIBROBLASTS (SFS) FROM ARTHRITIS MODEL MICE AND PATIENTS WITH RA. MICE WITH SF-SPECIFIC UHRF1 CONDITIONAL KNOCKOUT SHOWED MORE SEVERE ARTHRITIC PHENOTYPES THAN LITTERMATE CONTROLS. UHRF1-DEFICIENT SFS ALSO EXHIBITED ENHANCED APOPTOSIS RESISTANCE AND UPREGULATED EXPRESSION OF SEVERAL CYTOKINES, INCLUDING CCL20. IN PATIENTS WITH RA, DAS28, CRP, AND TH17 ACCUMULATION AND APOPTOSIS RESISTANCE WERE NEGATIVELY CORRELATED WITH UHRF1 EXPRESSION IN SYNOVIUM. FINALLY, RYUVIDINE ADMINISTRATION STABILIZED UHRF1 AMELIORATED ARTHRITIS PATHOGENESES IN A MOUSE MODEL OF RA. THIS STUDY DEMONSTRATED THAT UHRF1 EXPRESSED IN RA SFS CAN CONTRIBUTE TO NEGATIVE FEEDBACK MECHANISMS THAT SUPPRESS MULTIPLE PATHOGENIC EVENTS IN ARTHRITIS, SUGGESTING THAT TARGETING UHRF1 COULD BE ONE OF THE THERAPEUTIC STRATEGIES FOR RA. 2022 14 6245 35 THE MECHANISMS UNDERLYING CHRONIC INFLAMMATION IN RHEUMATOID ARTHRITIS FROM THE PERSPECTIVE OF THE EPIGENETIC LANDSCAPE. RHEUMATOID ARTHRITIS (RA) IS A CHRONIC INFLAMMATORY AUTOIMMUNE DISEASE THAT IS CHARACTERIZED BY SYNOVIAL HYPERPLASIA AND PROGRESSIVE JOINT DESTRUCTION. THE ACTIVATION OF RA SYNOVIAL FIBROBLASTS (SFS), ALSO CALLED FIBROBLAST-LIKE SYNOVIOCYTES (FLS), CONTRIBUTES SIGNIFICANTLY TO PERPETUATION OF THE DISEASE. GENETIC AND ENVIRONMENTAL FACTORS HAVE BEEN REPORTED TO BE INVOLVED IN THE ETIOLOGY OF RA BUT ARE INSUFFICIENT TO EXPLAIN IT. IN RECENT YEARS, ACCUMULATING RESULTS HAVE SHOWN THE POTENTIAL ROLE OF EPIGENETIC MECHANISMS, INCLUDING HISTONE MODIFICATIONS, DNA METHYLATION, AND MICRORNAS, IN THE DEVELOPMENT OF RA. EPIGENETIC MECHANISMS REGULATE CHROMATIN STATE AND GENE TRANSCRIPTION WITHOUT ANY CHANGE IN DNA SEQUENCE, RESULTING IN THE ALTERATION OF PHENOTYPES IN SEVERAL CELL TYPES, ESPECIALLY RASFS. EPIGENETIC CHANGES POSSIBLY PROVIDE RASFS WITH AN ACTIVATED PHENOTYPE. IN THIS PAPER, WE REVIEW THE ROLES OF EPIGENETIC MECHANISMS RELEVANT FOR THE PROGRESSION OF RA. 2016 15 4298 33 MICRORNA-146A GOVERNS FIBROBLAST ACTIVATION AND JOINT PATHOLOGY IN ARTHRITIS. SYNOVIAL FIBROBLASTS ARE KEY CELLS ORCHESTRATING THE INFLAMMATORY RESPONSE IN ARTHRITIS. HERE WE DEMONSTRATE THAT LOSS OF MIR-146A, A KEY EPIGENETIC REGULATOR OF THE INNATE IMMUNE RESPONSE, LEADS TO INCREASED JOINT DESTRUCTION IN A TNF-DRIVEN MODEL OF ARTHRITIS BY SPECIFICALLY REGULATING THE BEHAVIOR OF SYNOVIAL FIBROBLASTS. ABSENCE OF MIR-146A IN SYNOVIAL FIBROBLASTS DISPLAY A HIGHLY DEREGULATED GENE EXPRESSION PATTERN AND ENHANCED PROLIFERATION IN VITRO AND IN VIVO. DEFICIENCY OF MIR-146A INDUCES DEREGULATION OF TUMOR NECROSIS FACTOR (TNF) RECEPTOR ASSOCIATED FACTOR 6 (TRAF6) IN SYNOVIAL FIBROBLASTS, LEADING TO INCREASED PROLIFERATION. IN ADDITION, LOSS OF MIR-146A SHIFTS THE METABOLIC STATE OF FIBROBLASTS TOWARDS GLYCOLYSIS AND AUGMENTS THE ABILITY OF SYNOVIAL FIBROBLASTS TO SUPPORT THE GENERATION OF OSTEOCLASTS BY CONTROLLING THE BALANCE OF OSTEOCLASTOGENIC REGULATORY FACTORS RECEPTOR ACTIVATOR OF NF-KAPPAB LIGAND (RANKL) AND OSTEOPROTEGERIN (OPG). BONE MARROW TRANSPLANTATION EXPERIMENTS CONFIRMED THE IMPORTANCE OF MIR-146A IN THE RADIORESISTANT MESENCHYMAL COMPARTMENT FOR THE CONTROL OF ARTHRITIS SEVERITY, IN PARTICULAR FOR INFLAMMATORY JOINT DESTRUCTION. THIS STUDY THEREFORE IDENTIFIES MICRORNA-146A AS AN IMPORTANT LOCAL EPIGENETIC REGULATOR OF THE INFLAMMATORY RESPONSE IN ARTHRITIS. IT IS A CENTRAL ELEMENT OF AN ANTI-INFLAMMATORY FEEDBACK LOOP IN RESIDENT SYNOVIAL FIBROBLASTS, WHO ARE ORCHESTRATING THE INFLAMMATORY RESPONSE IN CHRONIC ARTHRITIS. MIR-146A RESTRICTS THEIR ACTIVATION, THEREBY PREVENTING EXCESSIVE TISSUE DAMAGE DURING ARTHRITIS. 2017 16 6110 27 THE EPIGENETIC ALTERATION OF SYNOVIAL CELL GENE EXPRESSION IN RHEUMATOID ARTHRITIS AND THE ROLES OF NUCLEAR FACTOR KAPPAB AND NOTCH SIGNALING PATHWAYS. RHEUMATOID ARTHRITIS (RA) IS A COMPLEX PROCESS OF CHRONIC AND PROGRESSIVE INFLAMMATION ASSOCIATED WITH ACTIVATION OF NUMEROUS SIGNALING MOLECULES AND TRANSCRIPTION FACTORS AND HYPERPROLIFERATION OF SYNOVIOCYTES OF THE AFFECTED JOINTS, ALTHOUGH THE GREATER PART OF ITS PATHOPHYSIOLOGICAL PROCESS IS EXPLAINED BY ACTIVATION OF NUCLEAR FACTOR KAPPAB (NF-KAPPAB). FOR EXAMPLE, THE SELF-PERPETUATING NATURE OF THE RHEUMATOID INFLAMMATION IS ASCRIBABLE TO OVEREXPRESSION OF THE PROINFLAMMATORY CYTOKINES TUMOR NECROSIS FACTOR ALPHA AND INTERLEUKIN-1BETA, KNOWN TO ELICIT THE ACTIVATION CASCADE FOR NF-KAPPAB AND ACTIVATOR PROTEIN-1 THAT ARE RESPONSIBLE FOR TRANSCRIPTIONAL INDUCTION OF THESE CYTOKINES AMONG OTHER TARGET GENES, WHICH CONFORM A POSITIVE FEEDBACK LOOP FOR CONTINUATION AND EXPANSION OF THE INFLAMMATORY RESPONSES. IN ADDITION, COMPARATIVE GENE EXPRESSION PROFILE ANALYSES HAVE REVEALED ACTIVATION OF A NUMBER OF GENES THAT EXPLAIN THE "TRANSFORMED-LIKE" PHENOTYPE OF SYNOVIOCYTES. AMONG THE GENES EXPRESSED IN RHEUMATOID SYNOVIOCYTES UPON INFLAMMATORY STIMULI, INDUCTION OF GENE EXPRESSION OF NOTCH PROTEINS AND ITS LIGAND HAVE BEEN FOUND. POSSIBLE ROLES OF NOTCH SIGNALING IN RA SYNOVIOCYTES ARE DISCUSSED. 2005 17 3699 33 INFLAMMATORY MEMORIES: IS EPIGENETICS THE MISSING LINK TO PERSISTENT STROMAL CELL ACTIVATION IN RHEUMATOID ARTHRITIS? RHEUMATOID ARTHRITIS (RA) IS A CHRONIC INFLAMMATORY DISEASE LEADING TO JOINT DESTRUCTION. SYNOVIAL FIBROBLASTS ARE RECOGNIZED AS KEY CELLS IN THE PATHOGENESIS OF RA SINCE THEY ATTRACT AND ACTIVATE IMMUNE CELLS AND PRODUCE MATRIX DEGRADING ENZYMES. MOST NOTABLY SYNOVIAL FIBROBLASTS FROM PATIENTS WITH RA ARE STABLY ACTIVATED AND PRODUCE HIGH LEVELS OF DISEASE-PROMOTING MOLECULES WITHOUT FURTHER STIMULATION BY IMMUNE CELLS. ACCUMULATING DATA SUGGEST THAT EPIGENETIC CHANGES IN STROMAL CELL POPULATIONS MIGHT BE CRUCIALLY INVOLVED IN THE PATHOLOGY OF RA AND OTHER CHRONIC INFLAMMATORY DISEASES. IN THE CURRENT REVIEW, WE DISCUSS THE MECHANISMS BY WHICH EPIGENETIC CHANGES MIGHT CAUSE THE STABLE ACTIVATION OF SYNOVIAL FIBROBLASTS IN RA AND HOW CHANGES IN THE EPIGENOME MIGHT ALTER IMMUNE FUNCTION AND INFLAMMATORY RESPONSE AND THEREBY PROMOTE THE DEVELOPMENT OF CHRONIC DISEASES. 2011 18 6657 38 UPREGULATED KAT7 IN SYNOVIAL FIBROBLASTS PROMOTES TH17 CELL DIFFERENTIATION AND INFILTRATION IN RHEUMATOID ARTHRITIS. RHEUMATOID ARTHRITIS (RA) IS A CHRONIC AUTOIMMUNE DISEASE INVOLVING MULTIPLE CELLULAR PARTICIPANTS, OF WHICH SYNOVIAL FIBROBLASTS (SFS) ARE TIGHTLY CONNECTED WITH THE DEVELOPMENT AND PROGRESSION OF RA. HERE, WE PROVIDE EVIDENCE CONFIRMING THAT KAT7, AN H4-SPECIFIC HISTONE ACETYLASE, IS UPREGULATED IN SFS OF RA PATIENTS, WHICH IS AT LEAST ATTRIBUTED TO THE STIMULATION BY RA-ASSOCIATED PROINFLAMMATORY CYTOKINES, SUCH AS TNF-ALPHA, IL-1BETA OR IFN-GAMMA. IN ADDITION, KAT7 OVEREXPRESSION IN CULTURED HUMAN FIBROBLAST-LIKE SYNOVIOCYTES (HFLSS) INDUCES IL-6 AND TGF-BETA EXPRESSION THROUGH AN EPIGENETIC MECHANISM, AND IN VITRO T HELPER 17 (TH17) CELL POLARIZATION CULTURED IN THESE SUPERNATANTS SHOWS PROMOTED CELL DIFFERENTIATION. MOREOVER, KAT7 OVEREXPRESSION IN HFLSS INDUCES CCL20 EXPRESSION VIA P44/42 MAPK PATHWAY, WHEREBY PROMOTING TH17 CELL MIGRATION. THESE TWO ACTIVITIES OF KAT7 IN RA SFS INDICATE ITS POTENTIAL ROLES IN ACCELERATING RA PATHOLOGY. OVERALL, THESE RESULTS DEMONSTRATE SOME CONNECTIONS BETWEEN KAT7 UPREGULATED IN RA SFS AND RA PROGRESSION AND PRESENT THE INHIBITION OF KAT7 ACTIVITY AS A NOVEL THERAPEUTIC TARGET FOR INTERFERING RA DISEASE. 2017 19 4684 32 NEW POTENTIAL THERAPEUTIC APPROACHES TARGETING SYNOVIAL FIBROBLASTS IN RHEUMATOID ARTHRITIS. SYNOVIAL CELLS PLAY A KEY ROLE IN JOINT DESTRUCTION DURING CHRONIC INFLAMMATION. IN PARTICULAR, ACTIVATED SYNOVIAL FIBROBLASTS (SFS) UNDERGO INTRINSIC ALTERATIONS LEADING TO AN AGGRESSIVE PHENOTYPE MEDIATING CARTILAGE DESTRUCTION AND BONE EROSION IN RHEUMATOID ARTHRITIS (RA). RECENT RESEARCH HAS REVEALED A NUMBER OF TARGETS TO CONTROL ARTHRITOGENIC CHANGES IN SFS. THEREFORE, IDENTIFICATION OF SF PHENOTYPES, CONTROL OF EPIGENETIC CHANGES, MODULATION OF CELLULAR FUNCTIONS, OR REGULATION OF THE ACTIVITY OF CATION CHANNELS AND DIFFERENT SIGNALING PATHWAYS HAS BEEN INVESTIGATED. ALTHOUGH MANY OF THESE APPROACHES HAVE SHOWN EFFICACY IN VITRO AND IN ANIMAL MODELS OF RA, FURTHER RESEARCH IS NEEDED TO SELECT THE MOST RELEVANT TARGETS FOR DRUG DEVELOPMENT. THIS REVIEW IS FOCUSED ON THE ROLE OF SFS AS A POTENTIAL STRATEGY TO DISCOVER NOVEL THERAPEUTIC TARGETS IN RA AIMED AT PRESERVING JOINT ARCHITECTURE AND FUNCTION. 2021 20 6869 43 [PATHOGENESIS OF RHEUMATOID ARTHRITIS]. RHEUMATOID ARTHRITIS (RA) IS AN AUTOIMMUNE SYSTEMIC DISEASE THAT PRIMARILY AFFECTS JOINTS. ETIOLOGY AND THE PATHOGENESIS OF RA ARE COMPLEX, INVOLVING MANY TYPES OF CELLS, AMONG OTHERS MACROPHAGES, T AND B CELLS, FIBRO- BLASTS, CHONDROCYTES AND DENDRITIC CELLS. DESPITE WELL DOCUMENTED ROLE OF MANY GENES AND EPIGENETIC MODIFICATIONS IN THE DEVELOPMENT AND EVOLUTION OF THE DISEASE, IN MOST RA PATIENTS THERE IS NO CLEAR PREDISPOSING FACTOR PRESENT. ENVIRONMENTAL FACTORS INVOLVED IN RA PATHOGENESIS ARE CIGARETTE SMOKE, INDUSTRIAL POLLUTANTS LIKE SILICA CRYSTALS, DISTURBANCES OF INTESTINAL, LUNG, AND ORAL MICROBIOTA AND SOME SPECIFIC BACTERIAL AND VIRAL INFECTIOUS AGENTS AND THEIR COMPONENTS. IN THE INITIAL DISEASE STAGE THERE ARE QUALITATIVE AND QUANTITATIVE DISTURBANCES OFPEPTIDE CITRULINATION AS WELL AS OTHER PROTEIN MODIFICATIONS, FOLLOWED BY ANTIGEN PRESENTING CELL (APC) (MACROPHAGES AND DENDRITIC CELLS) AND FIBROBLAST LIKE SYNOVIOCYTES (FLS) ACTIVATION. SOME MICROBES FOSTER THIS PROCESSES BY APC AND FLS DIRECT AND INDIRECT ACTIVATION. IN THE SECOND STAGE APC'S ELICIT SPECIFIC HUMORAL B CELL RE- SPONSE RESULTING IN SPECIFIC ANTIBODIES PRODUCTION AND T CELL AUTOREACTIVITY. INHERITED AND ACQUIRED DEFECTS IN T AND B CELL RESPONSES CAUSED BY REPEATED ACTIVATION OF INNATE IMMUNITY AS WELL AS LOSS OF TOLERANCE, ELICIT CHRONIC AUTOIMMUNE INFLAMMATION, PRIMARILY OF SYNOVIAL MEMBRANES, AND DEVELOPMENT OF CELLULAR PANUS. PATHOLOGIC ACTIVATION OF THE OSTEOCLASTS AND RELEASE OF THE IMMUNE SYSTEM EFFECTOR MOLECULES AND THE PROTEOLYTIC ENZYMES DAMAGE THE CARTILAGE, BONE AND TENDONS COMPOSITION AND STRUCTURE. PERSISTENT INFLAMMATION THROUGH ITS COMPLEX MECHANISMS RESULTS IN MANY SYSTEMIC AND EXTRAARTICULAR RA MANIFESTATIONS OF ALMOST ALL ORGAN SYSTEMS, RESULTING IN SEVERE COMPLICATIONS AND COMORBIDITIES SUCH AS RHEUMATOID LUNG, CARDITIS, VASCULITIS, CAHEXIA, ANEMIA, ACCELERATED ATHEROSCLEROSIS, MYOCARDIAL AND CEREBROVASCULAR VASCULAR DISEASE, LYMPHOMA, OSTEOPOROSIS, DEPRESSION ETC. ACCUMULATED COMPLICATIONS AND COMORBIDITIES FINALLY RESULT IN HANDICAP, SOCIAL DYSFUNCTION AND PREMATURE DEATH. 2014