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ID PMID Title PublicationDate abstract
16802368 Increased extracellular levels of the novel proinflammatory cytokine high mobility group b 2006 Jul OBJECTIVE: To investigate the expression of the novel proinflammatory cytokine high mobility group box chromosomal protein 1 (HMGB-1) in the salivary glands of patients with Sjögren's syndrome (SS) and patients with sicca symptoms. METHODS: Biopsy samples from the minor labial salivary glands of patients with SS, patients with sicca symptoms but no diagnosis of SS, and healthy controls were investigated. Expression of HMGB-1, tumor necrosis factor (TNF), and interleukin-1beta (IL-1beta) was analyzed using immunohistochemical staining on consecutive cryosections. RESULTS: Increased expression of HMGB-1 was observed among the large infiltrates of mononuclear cells found in biopsy samples from patients with SS, and the degree of extracellular HMGB-1 was significantly higher in patients with SS compared with patients with sicca symptoms and with healthy controls (P < 0.05 and P < 0.01, respectively). Cellular expression of TNF was increased in patients with SS and in patients with sicca symptoms. In addition, the level of secreted TNF was significantly higher in patients with SS than in healthy controls (P < 0.05). Intracellular expression of IL-1beta was detected in all groups, while extracellular IL-1beta was observed almost exclusively among the infiltrating mononuclear cells of patients with SS. CONCLUSION: The increased amount of extracellular HMGB-1 observed in salivary glands of patients with SS indicates that HMGB-1 is involved in the inflammatory process of the disease. This cytokine, along with TNF and IL-1beta, may form a proinflammatory loop that promotes the chronic features of the glandular inflammation in SS.
18172072 Small proline-rich protein 1B (SPRR1B) is a biomarker for squamous metaplasia in dry eye d 2008 Jan PURPOSE: Squamous metaplasia occurs in ocular surface diseases like Sjögren's syndrome (SS). It is a phenotypic change whereby epithelial cells initiate synthesis of squamous cell-specific proteins such as small proline-rich protein 1B (SPRR1B) that result in pathologic keratin formation on the ocular surface. The authors hypothesized that inflammation is a key inducer of pathologic keratinization and that SPRR1B represents an analytical biomarker for the study of the molecular mechanisms. METHODS: Real-time quantitative RT-PCR and immunohistochemistry were used to examine SPRR1B mRNA and protein in two different mouse models of dry eye and patients with SS. Adoptive transfer of mature lymphocytes from mice lacking the autoimmune regulator (aire) gene was performed to examine the role of inflammation as an inducer of squamous metaplasia. SPRR1B expression in response to several cytokines was examined in vitro, whereas the expression of cytokines IL1beta and IFNgamma was quantified in ocular tissues of aire-deficient mice and patients with SS. RESULTS: SPRR1B was increased across the ocular surface of mice with both desiccating stress and autoimmune-mediated, aqueous-deficient dry eye and in patients with SS. Adoptive transfer of CD4(+) T cells from aire-deficient mice to immunodeficient recipients caused advanced ocular surface keratinization. IL1alpha, IL1beta, IL6, IFNgamma, and TNFalpha induced SPRR1B expression in vitro and the local expression of IL1beta and IFNgamma was elevated in ocular tissues of patients with SS and aire-deficient mice. CONCLUSIONS: SPRR1B is a valid biomarker for the study of the molecular mechanisms of squamous metaplasia. There is a definitive link between inflammation and squamous metaplasia in autoimmune-mediated dry eye disease, with IL1beta and IFNgamma likely acting as key participants.
17057945 Anti-beta2-glycoprotein I in Sjogren's syndrome is associated with parkinsonism. 2007 May The nervous system may be involved in up to 30% of patients with Sjogren's syndrome (SS). We describe three patients with Sjogren's syndrome and a concomitant parkinsonian syndrome. Elevated titers of anti-beta2-glycoprotein I IgG were found in the serum of all three patients. This autoantibody is strongly associated with anticardiolipin (aCL) antibodies, antiphospholipid syndrome (APS), and thromboembolic phenomena, but its role in the pathogenesis of the parkinsonian disorder in SS is unclear. These patients may present a subtype of SS patients in which the presence of aCL antibodies is associated with central nervous system involvement predominantly in the basal ganglia.
19032782 Identification of possible candidate genes regulating Sjögren's syndrome-associated autoi 2008 INTRODUCTION: Sjögren syndrome (SjS) is a systemic autoimmune disease in which an immunological attack primarily against the salivary and lacrimal glands results in the loss of acinar cell tissue and function, leading to stomatitis sicca and keratoconjunctivitis sicca. In recent years, two genetic regions, one on chromosome 1 (designated autoimmune exocrinopathy 2 or Aec2) and the second on chromosome 3 (designated autoimmune exocrinopathy 1 or Aec1) derived from nonobese diabetic (NOD) mice, have been shown to be necessary and sufficient to replicate SjS-like disease in nonsusceptible C57BL/6 mice. METHODS: Starting with the SjS-susceptible C57BL/6-derived mouse, referred to as C57BL/6.NOD-Aec1Aec2, we generated a large set of recombinant inbred (RI) lines containing portions of Aec2 as a means of identifying more precisely the genetic elements of chromosome 1 responsible for disease development. RESULTS: Disease profiling of these RI lines has revealed that the SjS susceptibility genes of Aec2 lie within a region located at approximately 79 +/- 5 cM distal to the centromere, as defined by microsatellite markers. This chromosomal region contains several sets of genes known to correlate with various immunopathological features of SjS as well as disease susceptibility genes for both type 1 diabetes and systemic lupus erythematosus in mice. One gene in particular, tumor necrosis factor (ligand) superfamily member 4 (or Ox40 ligand), encoding a product whose biological functions correlate with both physiological homeostasis and immune regulations, could be a potential candidate SjS susceptibility gene. CONCLUSIONS: These new RI lines represent the first step not only in fine mapping SjS susceptibility loci but also in identifying potential candidate SjS susceptibility genes. Identification of possible candidate genes permits construction of models describing underlying molecular pathogenic mechanisms in this model of SjS and establishes a basis for construction of specific gene knockout mice.
18793250 Minor salivary gland immunohistology in the diagnosis of primary Sjögren's syndrome. 2009 Mar BACKGROUND: Focal lymphocytic infiltrates of minor salivary glands are considered target-organ related signs of Sjögren's syndrome. The percentages of plasma cells expressing IgA, IgG and IgM in minor salivary gland biopsies have also been suggested as useful in establishing a diagnosis of Sjögren's syndrome, and this study aimed at evaluating this method. METHODS: All biopsies from patients under investigation for Sjögren's syndrome (n = 210) at our department during 4 years were analyzed for IgA, IgG and IgM producing cells by immunohistochemistry, and related to Sjögren classification parameters. RESULTS: A focus score >or=1 was observed in 67/210 patients and the frequency of IgA producing cells was <70% in 42/210 patients. Sufficient clinical data for classification of disease were available for 57/210 patients. Patients were classified as having primary Sjögren's syndrome (pSS) (n = 9), secondary Sjögren's syndrome (sSS) (n = 12) or non-Sjögren's syndrome (non-SS) (n = 36). IgA expressing cells were significantly decreased (P < 0.01) and IgG expressing cells significantly increased (P < 0.02) in patients with pSS compared to non-SS. Also, increased numbers of salivary gland IgG producing plasma cells correlated with increased IgG serum levels (P < 0.001). However, there was no significant difference between sSS and non-SS with regard to IgA, IgG or IgM expressing cells in the glands. CONCLUSIONS: Our results support previous reports indicating the relevance of quantitative evaluation of Ig isotype expression in plasma cells in the clinical investigation of Sjögren's syndrome and further indicate a difference in plasma cell populations between pSS and sSS.
18381788 Diagnostic and prognostic significance of measuring antibodies to alpha-fodrin compared to 2008 May OBJECTIVE: To compare sensitivity and specificity of autoantibodies to alpha-fodrin with conventional anti-Ro and anti-La antibodies in patients with primary Sjögren's syndrome (pSS). Data on internal organ manifestations were correlated with presence of autoantibodies. METHODS: We collected clinical and laboratory data from 321 patients with pSS (Copenhagen criteria), of which 205 fulfilled the new American-European 2002 consensus criteria. Sera were tested for autoantibodies against alpha-fodrin and recombinant Ro-52, Ro-60, and La proteins. RESULTS: Antibodies to alpha-fodrin were not diagnostically superior to conventional anti-Ro/La testing. IgG anti-La had the highest specificity (97%). A highly significant association was found between presence of anti-La and internal organ manifestations (OR 6, 95% CI 2.99-12.03) or hematological abnormalities. The pattern of autoantibodies was relatively independent of disease duration, indicating that these antibodies appeared early in pSS, probably even years before the first symptoms were manifest. CONCLUSION: We could not confirm that antibodies to alpha-fodrin had higher specificity or sensitivity than anti-Ro/La. Anti-La antibodies were strongly correlated to organ involvement and cytopenias, and thus could serve as a prognostic marker in pSS.
19043715 Protein-losing gastroenteropathy associated with primary Sjögren's syndrome: a characteri 2009 May Protein-losing gastroenteropathy (PLGE) is a rare manifestation of primary Sjögren's syndrome (SS). We report a case of a 41-year-old Japanese man, who is the first male patient, with PLGE associated with primary SS. Although serum anti-SSA and SSB antibodies were detected, he had no subjective sicca symptoms. He had multiple annular erythema: a characteristic skin manifestation of Asian SS patients. A diagnosis of PLGE was made from results of (99m)Tc-labelled albumin scintigraphy and a faecal alpha-1-antitrypsin clearance test. Intravenous administration of high-dose glucocorticoid was not effective, but pulse methylprednisolone therapy alleviated disease manifestations. As all cases of PLGE associated with primary SS have been reported from East Asia, this complication could be essentially limited to Asian patients.
17004051 [Sjögren's syndrome. Current aspects from a rheumatological point of view]. 2006 Oct Sjögren's syndrome is an autoimmune disease of the exocrine glands characterized by the leading symptoms of keratoconjunctivitis and stomatitis sicca based on a complex pathogenesis. The prevalence is about 0.5-1%; primary Sjögren's syndrome is differentiated from secondary Sjögren's syndrome associated with other autoimmune disorders. The diagnosis is established by the presence of subjective complaints and objective evidence of sicca symptoms, anti-Ro(SSA)/La(SSB) antibodies, and/or focal lymphocytic infiltration of the glandular tissue. In addition to the typical sicca symptomatology, which is managed symptomatically by substitution and stimulation therapy, some patients exhibit extraglandular manifestations. Complaints involving the musculoskeletal system and inner ear dominate and are treated by the rheumatologist. The indication for base therapy is tailored to individual needs, but the efficacy of this approach has not been established in studies. About 5-10% of the patients with primary Sjögren's syndrome develop a B-cell non-Hodgkin's lymphoma. The disease requires interdisciplinary management including, among others, ophthalmologists, dentists, and otorhinolaryngologists, depending on the clinical picture.
16391885 Sjögren syndrome in a child: favorable response of the arthritis to TNFalpha blockade. 2006 Sep Tumor necrosis factor alpha (TNFalpha) blockade has recently been found to be ineffective in treating glandular and extraglandular manifestations of adult Sjögren syndrome (SS), including arthralgia and arthritis. We report a girl who developed purpura, polyarthritis, uveitis, and severe dental caries in the first year of life and optic neuritis by age three. SS was diagnosed at 11 years of age, when severe hypokalemic renal tubular acidosis developed during infliximab treatment for arthritis. In contrast to her other disease manifestations, the arthritis responded remarkably well to TNFalpha blockade, suggesting that TNFalpha blockers may have a role in the treatment of arthritis with pediatric SS.
15980937 A case of Sjögren's syndrome with acute transverse myelitis and polyneuropathy in a patie 2006 Feb Acute transverse myelitis (ATM) is an inflammatory process involving a restricted area of the spinal cord. The usually dramatic presentation with rapidly progressive symptoms involving motor, sensory, and autonomic functions makes ATM a medical emergency. ATM has been cited as a rare and unusual complication of Sjögren's syndrome, but early diagnosis and aggressive treatment might improve the prognosis. I report a case of Sjögren's syndrome with ATM and polyneuropathy in a patient free of sicca symptoms and having skin lesions and synovitis as the initial manifestations.
18383359 CD200-Fc, a novel antiarthritic biologic agent that targets proinflammatory cytokine expre 2008 Apr OBJECTIVE: The CD200 receptor (CD200R) is an inhibitory receptor expressed by myeloid cells that is postulated to play an important role in regulation of the immune system. The purpose of this study was to evaluate the efficacy of a soluble ligand of CD200R in established collagen-induced arthritis (CIA) in mice and to analyze changes in cytokine expression following therapy in order to understand its primary mechanism of action. METHODS: Arthritis was induced in DBA/1 mice, and CD200-Fc fusion protein, an isotype control monoclonal antibody, or TNFR-Fc fusion protein was administered over a period of 10 days (total of 4 doses). Cytokine expression in the joint was assessed by flow cytometry, enzyme-linked immunosorbent assay, and quantitative real-time polymerase chain reaction. RESULTS: CD200-Fc significantly reduced the severity of established arthritis at the clinical and histologic levels. The therapeutic effect of CD200-Fc at 1 mg/kg was comparable with that of TNFR-Fc at 4 mg/kg. CD200R was found to be expressed in arthritic synovia and in lymph nodes, yet no changes in T cell cytokine levels (interferon-gamma, interleukin-5 [IL-5], IL-10, IL-17) were detected after CD200-Fc therapy. There was no evidence of an expansion of forkhead box P3-positive regulatory T cells or a change in serum anticollagen IgG1 and IgG2a levels. However, administration of CD200-Fc markedly decreased the expression of messenger RNA for tumor necrosis factor alpha, IL-1beta, IL-10, and matrix metalloproteinase 13 in the joint to the same extent as administration of TNFR-Fc. CONCLUSION: CD200-Fc is an effective therapeutic agent in established CIA that targets proinflammatory cytokine expression in the joint without any obvious systemic immunosuppressive effects. Our findings indicate that CD200-Fc has considerable potential as a novel therapeutic agent in rheumatoid arthritis in humans.
18936206 Green tea protects rats against autoimmune arthritis by modulating disease-related immune 2008 Nov Green tea, a product of the dried leaves of Camellia sinensis, is the most widely consumed beverage in the world. The polyphenolic compounds from green tea (PGT) possess antiinflammatory properties. We investigated whether PGT can afford protection against autoimmune arthritis and also examined the immunological basis of this effect using the rat adjuvant arthritis (AA) model of human rheumatoid arthritis (RA). AA can be induced in Lewis rats (RT.1(l)) by immunization with heat-killed Mycobacterium tuberculosis H37Ra (Mtb), and arthritic rats raise a T cell response to the mycobacterial heat-shock protein 65 (Bhsp65). Rats consumed green tea (2-12 g/L) in drinking water for 1-3 wk and then were injected with Mtb to induce disease. Thereafter, they were observed regularly and graded for signs of arthritis. Subgroups of these rats were killed at defined time points and their draining lymph node cells were harvested and tested for T cell proliferative and cytokine responses. Furthermore, the sera collected from these rats were tested for anti-Bhsp65 antibodies. Feeding 8 g/L PGT to Lewis rats for 9 d significantly reduced the severity of arthritis compared with the water-fed controls. Interestingly, PGT-fed rats had a lower concentration of the proinflammatory cytokine interleukin (IL)-17 but a greater concentration of the immunoregulatory cytokine IL-10 than controls. PGT feeding also suppressed the anti-Bhsp65 antibody response. Thus, green tea induced changes in arthritis-related immune responses. We suggest further systematic exploration of dietary supplementation with PGT as an adjunct nutritional strategy for the management of RA.
18235973 Co-expression of IL-18 binding protein and IL-4 regulates Th1/Th2 cytokine response in mur 2008 Feb We constructed a recombinant adenoviral vector containing a murine interleukin (IL)-18 binding protein (mIL-18BP) and murine IL-4 (mIL-4) fusion gene (AdmIL-18BP/mIL-4) and used a gene therapy approach to investigate the role of IL-18BP and IL-4 in modulating the T-helper1 and T-helper2 (Th1/Th2) balance in mice with collagen-induced arthritis (CIA). Mice with CIA were intra-articularly injected with 107 pfu/6 microl of either AdmIL-18BP/mIL-4, or a control adenovirus, or with the control vehicle (phosphate-buffered saline). After intra-articular gene therapy with AdmIL-18BP/mIL-4, the serum levels of tumor necrosis factor-alpha (TNF-alpha), gamma-interferon (IFN-gamma), IL-4, IL-10, and IL-18 in mice with CIA were assessed by ELISA. IFN-gamma-expressing and IL-4-expressing CD4+ T cells from mice splenocytes were monitored by flow cytometry. Mice with CIA at weeks 1, 2, and 4 after intra-articular injection of AdmIL-18BP/mIL-4 showed significantly increased serum concentrations of IL-4 and IL-10 (P<0.01 at all time points) but greatly decreased serum concentrations of IFN-gamma, TNF-alpha, and IL-18 (P<0.01 at all time points) compared to both the control adenovirus and phosphate-buffered saline control groups. The percentage of IFN-gamma-producing CD4+ T cells was significantly decreased in response to local AdmIL-18BP/mIL-4 treatment. The percentage of IL-4-producing CD4+ T cells increased significantly at 1 week after local injection of AdmIL-18BP/mIL-4 then returned to normal by week 4. These data indicated the significant modifying effects on the Th1/Th2 imbalance in murine CIA produced by local overexpression of IL-18BP and IL-4. Combination treatment with IL-18BP and IL-4 is a promising potential therapy for rheumatoid arthritis.
19041137 A novel recombinant peptide containing only two T-cell tolerance epitopes of chicken type 2009 Feb Immunotherapy of rheumatoid arthritis (RA) using oral-dosed native chicken or bovine type II collagen (nCII) to induce specific immune tolerance is an attractive strategy. However, the majority of clinical trials of oral tolerance in human diseases including RA in recent years have been disappointing. Here, we describe a novel recombinant peptide rcCTE1-2 which contains only two tolerogenic epitopes (CTE1 and CTE2) of chicken type II collagen (cCII). These are the critical T-cell determinants for suppression of RA that were first developed and used to compare its suppressive effects with ncCII on the collagen-induced arthritis (CIA) model. The rcCTE1-2 was produced using the prokaryotic pET expression system and purified by Ni-NTA His affinity chromatography. Strikingly, our results showed clearly that rcCTE1-2 was as efficacious as ncCII at the dose of 50 microg/kg/d. This dose significantly reduced footpad swelling, arthritic incidence and scores, and deferred the onset of disease. Furthermore, rcCTE1-2 of 50 microg/kg/d could lower the level of anti-nCII antibody in the serum of CIA animals, decrease Th1-cytokine INF-gamma level, and increase Th3-cytokine TGF-beta(1) produced level by spleen cells from CIA mice after in vivo stimulation with ncCII. Importantly, rcCTE1-2 was even more potent than native cCII, which was used in the clinic for RA. Equally importantly, the findings that the major T-cell determinants of cCII that are also recognized by H-2(b) MHC-restricted T cells have not previously been reported. Taken together, these results suggest that we have successfully developed a novel recombinant peptide rcCTE1-2 that can induce a potent tolerogenic response in CIA.
16477328 Inflammation, the key to much pathology. Highlights from the 7th World Congress on Inflamm 2006 Feb 1 From the World Congress on Inflammation, held August 20-24, 2005 in Melbourne, Australia, new targets and new drugs for inflammation of the respiratory system (asthma, allergic rhinitis, chronic obstructive pulmonary disease and cystic fibrosis), inflammatory bowel disease (ulcerative colitis and Crohn's disease), arthritis (rheumatoid and osteoarthritis), atherosclerosis and cancer are discussed.
18466603 A nonparametric regression-based linkage scan of rheumatoid factor-IgM using sib-pair squa 2007 Parametric linkage methods for quantitative trait locus mapping require explicit specification of the probability model of the quantitative trait and hence can lead to misleading linkage inferences when the model assumptions are not valid. Ghosh and Majumder developed a nonparametric regression method based on kernel-smoothing for linkage mapping of quantitative trait locus using squared differences in trait values of independent sib pairs, which is relatively more robust than parametric methods with respect to violations in distributional assumptions. In this study, we modify the above mentioned nonparametric regression method by considering local linear polynomials instead of the Nadaraya-Watson estimator and squared sums of sib-pair trait values in addition to squared differences to perform a genome-wide scan of rheumatoid factor-IgM levels on sib pairs in the Genetic Analysis Workshop 15 simulated data set. We obtain significant evidence of linkage very close to the quantitative trait locus controlling for RF-IgM. We find that the simultaneous use of squared differences and squared sums increases the power to detect linkage compared to using only squared differences. However, because of all the sib pairs are selected for rheumatoid arthritis, there is reduced variance of RF-IgM values, and empirical power to detect linkage is not very high. We also compare the performance of our method with two linear regression approaches: the classical Haseman-Elston method using squared sib-pair trait differences and its extension proposed by Elston et al. using mean-corrected sib-pair cross-products. We find that the proposed nonparametric method yields more power than the linear regression approaches.
16219353 The 5q- syndrome and autoimmune phenomena: report of three cases. 2006 Apr Myelodysplastic syndrome is a clonal hematopoietic stem cell disorder characterized by ineffective hematopoiesis, peripheral cytopenias and an additional risk to evolve to acute leukemia in up to 30% of the cases. Autoimmune manifestations as vasculitis, pyoderma gangrenosum, hemolytic anemia, immune thrombocytopenia, rheumatoid arthritis as well as positive anti-nuclear factor and rheumatoid factor have been reported in 13-30% of MDS patients. The aim of this report is to present three patients with 5q- syndrome who presented different autoimmune serological and clinical phenomena and review the literature. Patient 1 showed a focal and segmental glomerulosclerosis (FSGE) in the course of a MDS. Renal involvement in MDS as autoimmune phenomenon is rare and few reports have documented different forms of glomerular diseases in adults with MDS. Patients 2 and 3 showed a rheumatoid factor of 1/140 and the direct Coomb's test positive (3+), respectively, but without evidence of clinical autoimmune manifestation. In conclusion, patients with the 5q- syndrome experience a relative benign disease course extending over several years. We believe that careful follow-up of patients with autoimmune manifestations as here reported is important to detect any unexpected outcome.
17578055 Valve repair for mitral insufficiency secondary to idiopathic juvenile polyarthritis. 2007 May A female patient in whom idiopathic rheumatoid polyarthritis was diagnosed at the age of 8 years required surgery for severe mitral valve insufficiency 16 years later. Intraoperative analysis revealed a fibrotic endocarditis involving mainly the posterior leaflet. Granulomatous vegetations as well as a large thrombus which filled the left ventricular apex and simulated endomyocardial fibrosis were noted. Valve repair was achieved using an anterior leaflet augmentation with a patch of mitral homograft associated with a prosthetic ring annuloplasty. Postoperatively, a severe pericardial effusion required surgical drainage. Eight years later, the patient had no cardiac symptoms and echocardiography confirmed a normally functioning mitral valve.
18987599 Glucomannan in prevention of oxidative stress and inflammation occurring in adjuvant arthr 2008 Oct OBJECTIVES: The aim of this study was to evaluate the effects of a biological response modifier, glucomannan (GM), isolated from Candida utilis, on the progress of adjuvant arthritis in Lewis rats. METHODS: Adjuvant arthrithis was induced in Lewis rats by a single intradermal injection of Mycobacterium butyricum. GM was administered in two different doses of 5 and 7.5 mg/kg b.w. The treatment involved daily oral or intraperitoneal administration of the substance from day 0, i.e. the day of immunization to the end of the experiment - day 28. Cyclosporin A was used as a therapeutic standard in daily oral dose of 2.5 mg/kg b.w. The following parameters were monitored: hind paw volume, total antioxidant status, protein carbonyl groups, activity of N-acetyl-beta-D-glucosaminidase in plasma, lysozyme and peroxidase activity of peritoneal macrophages and activity of gamma-glutamyltransferase in homogenates of spleen, hind paw muscle and hind paw joint. RESULTS: Beneficial action of GM was revealed mainly in hind paw volume decrease. Further decrease of the activity of the enzyme gamma glutamyltransferase (GGT) in the spleen, hind paw joint and muscle tissue homogenates, decrease of the plasmatic activity of N-acetyl-beta-D-glucosaminidase (NAGA), and finally suppression of lysozyme and peroxidase activity assessed in peritoneal macrophages were observed in arthritic animals treated with GM. All these findings speak in favor of the anti-inflammatory activity of glucomannan. Moreover, a significant improvement of the arthritis induced suppression of total antioxidant status and decrease of the level of the arthritis-associated protein carbonyls in plasma were detected. CONCLUSIONS: The important characteristics of GM isolated from Candida utilis, such as good water solubility and relatively small molecular weight, along with the observed in vivo anti-inflammatory and antioxidant effects, appear to be promising features for its prospective use as a natural agent in prevention and supplementary therapy of rheumatoid arthritis.
16424221 Essential role of MAPK phosphatase-1 in the negative control of innate immune responses. 2006 Feb 1 TLR-induced innate immunity and inflammation are mediated by signaling cascades leading to activation of the MAPK family of Ser/Thr protein kinases, including p38 MAPK, which controls cytokine release during innate and adoptive immune responses. Failure to terminate such inflammatory reactions may lead to detrimental systemic effects, including septic shock and autoimmunity. In this study, we provide genetic evidence of a critical and nonredundant role of MAPK phosphatase (MKP)-1 in the negative control of MAPK-regulated inflammatory reactions in vivo. MKP-1-/- mice are hyperresponsive to low-dose LPS-induced toxicity and exhibit significantly increased serum TNF-alpha, IL-6, IL-12, MCP-1, IFN-gamma, and IL-10 levels after systemic administration of LPS. Furthermore, absence of MKP-1 increases systemic levels of proinflammatory cytokines and exacerbates disease development in a mouse model of rheumatoid arthritis. When activated through TLR2, TLR3, TLR4, TLR5, and TLR9, bone marrow-derived MKP-1-/- macrophages exhibit increased cytokine production and elevated expression of the differentiation markers B7.2 (CD86) and CD40. MKP-1-deficient macrophages also show enhanced constitutive and TLR-induced activation of p38 MAPK. Based on these findings, we propose that MKP-1 is an essential component of the intracellular homeostasis that controls the threshold and magnitude of p38 MAPK activation in macrophages, and inflammatory conditions accentuate the significance of this regulatory function.