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Objectives: For children with Kawasaki disease (KD) at high risk of developing coronary artery lesions and requiring retreatment with intravenous immunoglobulin (IVIG), the availability of accurate prediction models remains limited because of inconsistent variables and unsatisfactory prediction results. We aimed to construct models to predict patient's probability of IVIG retreatment combining children's individual inflammatory characteristics. Methods: Clinical manifestations and laboratory examinations of 266 children with KD were retrospectively analysed to build a development cohort data set (DC) and a validation cohort data set (VC). In the DC, binary logistic regression analyses were performed using R language. Nomograms and receiver operating curves were plotted. The concordance index (C index), net reclassification index, integrated discrimination improvement index and confusion matrix were applied to evaluate and validate the models. Results: Models_5V and _9V were established. Both contained variables including the percentages of CD8+ T cells, CD4+ T cells, CD3+ T cells, levels of interleukin (IL)‐2R and CRP. Model_9V additionally included variables for IL‐6, TNF‐α, NT‐proBNP and sex, with a C index of 0.86 (95% CI 0.79–0.92). When model_9V was compared with model_5V, the NRI and IDI were 0.15 (95% CI 0.01–0.30, P < 0.01) and 0.07 (95% CI 0.02–0.12, P < 0.01). In the VC, the sensitivity, specificity and precision of model_9V were 1, 0.875 and 0.667, while those of model_5V were 0.833, 0.875 and 0.625. Conclusion: Model_9V combined cytokine profiles and lymphocyte subsets with clinical characteristics and was superior to model_5V achieving satisfactory predictive power and providing a novel strategy early to identify patients who needed IVIG retreatment. [ABSTRACT FROM AUTHOR]

Aim To evaluate CD4+ CD28+ and CD8+ T-cell genes and the gene expression of IFN-γ, TNF-α, IL-1-β, IL-17A, IL-10, CCL-2/ MCP-1, CCL-4, CCL-5 ( RANTES), CXCR4, CCR5 and RANKL from cells in the periapical interstitial fluid from root canal infections in healthy patients ( HIV−) and HIV-positive individuals ( HIV+). Methodology Subjects included 20 HIV− and 23 HIV+ patients referred to the School of Dentistry at the Universidade Federal de Minas Gerais (Belo Horizonte, MG, Brazil). Almost all HIV+ patients were undergoing highly active antiretroviral therapy ( HAART). Clinical samples were taken from teeth with pulp necrosis, and no patients had acute periapical symptoms at the time of the appointments. After cleaning and drying, 3 paper points were introduced into the root canal, passing passively through the root apex (2 mm) into the periapical tissues for 1 min. The samples were collected immediately after root canal cleaning and 7 days later (restrained root canal bacterial load) to characterize those gene expressions using real-time PCR. Results Significantly higher levels of CD4+ CD28+ and CD8+ T cells in teeth with restrained bacterial loads (second collection) compared with the first collection were observed in both HIV− and HIV+ samples. In HIV− patients, an increase in IL-10 and CXCR4 expression was demonstrated as well as a decrease in pro-inflammatory cytokines such as RANKL, IFN-γ, IL1-β and CCL5. However, in HIV+ patients an increase in cytokines IFN-γ, IL-1-β, TNF-α and IL-17A, and chemokines CCL-2, CXCR4 and CCR5 were observed. The chemokine CCL-5 was not detected in HIV+ individuals. Conclusions These findings suggest that after reducing the root canal bacterial load in HIV− individuals an anti-inflammatory response is generated whilst in HIV+ patients a pro-inflammatory response is sustained in the periapical area. [ABSTRACT FROM AUTHOR]

Please cite this paper as: In vitro and in vivo analysis of pro- and anti-inflammatory effects of weak and strong contact allergens. Experimental Dermatology 2010; : 1007-1013. Inflammation is a crucial step in the development of allergic contact dermatitis. The primary contact with chemical allergens, called sensitization, and the secondary contact, called elicitation, result in an inflammatory response in the skin. The ability of contact allergens to induce allergic contact dermatitis correlates to a great extent with their inflammatory potential. Therefore, the analysis of the sensitizing potential of a putative contact allergen should include the examination of its ability and potency to cause an inflammation. In this study, we examined the inflammatory potential of different weak contact allergens and of the strong sensitizer 2,4,6-trinitrochlorobenzene (TNCB) in vitro and in vivo using the contact hypersensitivity model, the mouse model for allergic contact dermatitis. Cytokine induction was analysed by PCR and ELISA to determine mRNA and protein levels, respectively. Inflammation-dependent recruitment of skin-homing effector T cells was measured in correlation with the other methods. We show that the sensitizing potential of a contact allergen correlates with the strength of the inflammatory response. The different methods used gave similar results. Quantitative cytokine profiling may be used to determine the sensitizing potential of chemicals for hazard identification and risk assessment. [ABSTRACT FROM AUTHOR]

Background: Voltage‐gated calcium (Cav1) channels contribute to T‐lymphocyte activation. Cav1.2 and Cav1.3 channels are expressed in Th2 cells but their respective roles are unknown, which is investigated herein. Methods: We generated mice deleted for Cav1.2 in T cells or Cav1.3 and analyzed TCR‐driven signaling. In this line, we developed original fast calcium imaging to measure early elementary calcium events (ECE). We also tested the impact of Cav1.2 or Cav1.3 deletion in models of type 2 airway inflammation. Finally, we checked whether the expression of both Cav1.2 and Cav1.3 in T cells from asthmatic children correlates with Th2‐cytokine expression. Results: We demonstrated non‐redundant and synergistic functions of Cav1.2 and Cav1.3 in Th2 cells. Indeed, the deficiency of only one channel in Th2 cells triggers TCR‐driven hyporesponsiveness with weakened tyrosine phosphorylation profile, a strong decrease in initial ECE and subsequent reduction in the global calcium response. Moreover, Cav1.3 has a particular role in calcium homeostasis. In accordance with the singular roles of Cav1.2 and Cav1.3 in Th2 cells, deficiency in either one of these channels was sufficient to inhibit cardinal features of type 2 airway inflammation. Furthermore, Cav1.2 and Cav1.3 must be co‐expressed within the same CD4+ T cell to trigger allergic airway inflammation. Accordingly with the concerted roles of Cav1.2 and Cav1.3, the expression of both channels by activated CD4+ T cells from asthmatic children was associated with increased Th2‐cytokine transcription. Conclusions: Thus, Cav1.2 and Cav1.3 act as a duo, and targeting only one of these channels would be efficient in allergy treatment. [ABSTRACT FROM AUTHOR]

Background and Purpose: The immunomodulatory effects of alpha-fetoprotein (AFP) on lymphocytes and macrophages have been described in vitro and in vivo. Recombinant forms of human AFP have been proposed as potential therapeutic entities for the treatment of autoimmune diseases. We examined the effects of embryonic and recombinant human AFP on the spontaneous, UVA- and cytokine-induced pro-inflammatory responses of human keratinocytes.Experimental Approach: Cultures of primary and immortalized human keratinocytes (HaCaT) and human blood T lymphocytes were used. The effects of AFP on cytokine expression were studied by bioplexed elisa and quantitative reverse transcriptase polymerase chain reaction assay. Kinase and nuclear factor kappa B (NFkappaB) phosphorylation were quantified by intracellular elisa. Nuclear activator protein 1 and NFkappaB DNA binding activity was measured by specific assays. Nitric oxide and H(2)O(2) production and redox status were assessed by fluorescent probe and biochemical methods.Key Results: All forms of AFP enhanced baseline expression of cytokines, chemokines and growth factors. AFP dose-dependently increased tumour necrosis factor alpha-stimulated granulocyte macrophage colony stimulating factor and interleukin 8 expression and decreased tumour necrosis factor alpha-induced monocyte chemotactic protein 1 and IP-10 (interferon gamma-produced protein of 10 kDa) expression. AFP induced a marked activator protein 1 activation in human keratinocytes. AFP also increased H(2)O(2) and modulated nitrite/nitrate levels in non-stimulated keratinocytes whereas it did not affect these parameters or cytokine release from UVA-stimulated cells. Phosphorylation of extracellular signal-regulated kinase (ERK1/2) and Akt1 but not NFkappaB was activated by AFP alone or by its combination with UVA.Conclusions and Implications: Exogenous AFP induces activation of human keratinocytes, with de novo expression of a number of pro-inflammatory mediators and modulation of their pro-inflammatory response to cytokines or UVA. AFP may modulate inflammatory events in human skin. [ABSTRACT FROM AUTHOR]

While there is a vast array of aetiologies that may lead to chronic pruritus, recent data suggests that many of these conditions share similar interactions between keratinocytes, nerves, and the immune system. Specifically, the type 2 immune response, including Th2 T Cells and their related cytokines, has been noted to play a major role in the development of pruritus in a variety of itchy conditions. To date, atopic dermatitis is the most striking example of this pathogenesis. However, the body of literature supporting its role in many other itchy conditions, including other inflammatory, bullous, as well as systemic diseases, continues to grow. In addition, new treatments targeting this type 2 immune system continue to be developed and investigated. In the current review, we present the current body of literature supporting the role of the type 2 immune response in itchy conditions beyond atopic dermatitis as well as potential therapeutic options that target this pathway for chronic itch. [ABSTRACT FROM AUTHOR]

Coronavirus disease 2019 (COVID‐19) is a respiratory disorder caused by the highly contagious severe acute respiratory syndrome coronavirus 2. The immunopathological characteristics of patients with COVID‐19, either systemic or local, have not been thoroughly studied. In the present study, we analysed both the changes in the number of various immune cell types as well as cytokines important for immune reactions and inflammation. Our data indicate that patients with severe COVID‐19 exhibited an overall decline of lymphocytes including CD4+ and CD8+ T cells, B cells and natural killer cells. The number of immunosuppressive regulatory T cells was moderately increased in patients with mild COVID‐19. Interleukin‐6 (IL‐6), IL‐10 and C‐reactive protein were remarkably up‐regulated in patients with severe COVID‐19. In conclusion, our study shows that the comprehensive decrease of lymphocytes, and the elevation of IL‐6, IL‐10 and C‐reactive protein are reliable indicators of severe COVID‐19. [ABSTRACT FROM AUTHOR]

Seborrhoeic Dermatitis (SD) is a common inflammatory skin disorder, but its molecular pathogenesis remains elusive. Previously, we have established the Mpzl3 knockout (−/−) mice as a model for SD. In this study, we focused on early phases of skin inflammation and determined the cytokine profiles and identified immune cell types in the lesional skin in the Mpzl3 −/− mice. Using flow cytometry, we detected a significant increase of CD45+ leucocytes, CD3+ T lymphocytes and especially γδ T cells but not αβ T cells in the lesional skin compared to control. We also detected high levels of IL‐17 and determined that the γδ T cells were a major contributing source. CD3+ and γδ T cell localization in the skin was verified by indirect immunofluorescent staining. Since neither γδ T cells nor IL‐17 had been implicated in SD, our study provides novel insights into the role of MPZL3 in the pathogenesis of SD‐like skin inflammation. [ABSTRACT FROM AUTHOR]

Summary: Signal transducers and activators of transcription (STATs) are key molecular determinants of T‐cell fate and effector function. Several inflammatory diseases are characterized by an altered balance of T‐cell phenotypes and cytokine secretion. STATs, therefore, represent viable therapeutic targets in numerous pathologies. However, the underlying mechanisms by which the same STAT proteins regulate both the development of different T‐cell phenotypes and their plasticity during changes in extracellular conditions remain unclear. In this study, we investigated the STAT‐mediated regulation of T‐cell phenotype formation and plasticity using mathematical modelling and experimental data for intracellular STAT signalling proteins. The close fit of our model predictions to the experimental data allows us to propose a potential mechanism for T‐cell switching. According to this mechanism, T‐cell phenotype switching is the result of the relative redistribution of STAT dimer complexes caused by the extracellular cytokine‐dependent STAT competition effects. The developed model predicts that the balance between the intracellular STAT species defines the amount of the produced cytokines and thereby T‐cell phenotypes. The model predictions are consistent with the experimentally observed interferon‐γ to interleukin‐10 switching that regulates human T helper type 1/type 1 regulatory T‐cell responses. The proposed model is applicable to a number of STAT signalling circuits. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: In the pathogenesis of asthma, an imbalance between helper T (Th) 1/Th2 and Th17/Treg cells is believed to play a key role in asthmatic inflammatory responses. Some studies indicated that zinc deficiency increases inflammatory factor production and worsens asthma. However, the effects of zinc on T cell profiles to reduce inflammatory response remain unclear. Objectives: We investigated the beneficial effects of zinc on isolated cell populations and cytokine levels from patients with asthma. Methods: Thirty‐six individuals Dermatophagoides pteronyssinus (Der p)‐allergic and 31 healthy subjects were enrolled in the study, and peripheral blood mononuclear cells (PBMCs) were collected. Harvested PBMCs were stimulated with recombinant Der p antigen in the presence or absence of zinc sulfate (25 μM or 50 μM) for 48 h. Cell surface markers and intracellular cytokine levels were examined by flow cytometry. The pro‐inflammatory factors in plasma and culture supernatants were measured by commercial enzyme‐linked immunosorbent assay. Results: Zinc sulfate dramatically reduced the proportions of Th2 and Th17 cells, but increased that of Th1 and Treg cells. Zinc sulfate also markedly reduced the levels of interleukin (IL)‐4 and IL‐17, but increased the levels of IFN‐γ. Conclusions: Zinc ameliorates the imbalance in T cell profiles and could be a potential adjuvant therapy for Der p‐induced allergic hypersensitivity. [ABSTRACT FROM AUTHOR]

Background and Purpose: Myocarditis is an inflammatory and autoimmune cardiovascular disease that causes dilated myocardiopathy and is responsible for high morbidity and mortality worldwide. Cortistatin is a neuropeptide produced by neurons and cells of the immune and vascular systems. Besides its action in locomotor activity and sleep, cortistatin inhibits inflammation in different experimental models of autoimmune diseases. However, its role in inflammatory cardiovascular disorders is unexplored. Here, we investigated the therapeutic effects of cortistatin in a well-established preclinical model of experimental autoimmune myocarditis (EAM).Experimental Approach: We induced EAM by immunization with a fragment of cardiac myosin in susceptible Balb/c mice. Cortistatin was administered i.p. starting 7, 11 or 15 days after EAM induction. At day 21, we evaluated heart hypertrophy, myocardial injury, cardiac inflammatory infiltration and levels of serum and cardiac inflammatory cytokines, cortistatin and autoantibodies. We determined proliferation and cytokine production by heart draining lymph node cells in response to cardiac myosin restimulation.Key Results: Systemic injection of cortistatin during the effector phase of the disease significantly reduced its prevalence and signs of heart hypertrophy and injury (decreased the levels of brain natriuretic peptide) and impaired myocardial inflammatory cell infiltration. This effect was accompanied by a reduction in self-antigen-specific T-cell responses in lymph nodes and in the levels of cardiomyogenic antibodies and inflammatory cytokines in serum and myocardium. Finally, we found a positive correlation between cardiac and systemic cortistatin levels and EAM severity.Conclusions and Implications: Cortistatin emerges as a new candidate to treat inflammatory dilated cardiomyopathy. [ABSTRACT FROM AUTHOR]

Aim In normal pregnancy, the Th1 subtype, responsible for the production of inflammatory cytokines, is reduced, and the Th2 subtype is increased to prohibit inflammation. In pre-eclampsia, the Th1 cell population is increased; thus, subsequent inflammation and trophoblast destruction occur. Polymorphisms in the Fas and Fas Ligand ( FasL) promoter regions can influence Fas and FasL expression and accused to increase of Th1 subtype. Methods DNA samples from 153 pregnant women with pre-eclampsia and 140 controls were genotyped through polymerase chain reaction-restriction fragment length polymorphism. A Fisher's exact test was used to compare the distribution of individual polymorphisms. Results Fas-1377 AA, AG and GG genotypes were observed in 2.61%, 18.30% and 79.08% in the pre-eclampsia group opposed to 0%, 27.14% and 72.85% in the control group ( P = 0.037), respectively. Fas-670 AA, AG and GG genotypes were observed in 37.9%, 41.8% and 20.3% of pre-eclampsia patients compared with 33.6%, 50.7% and 15.7% in healthy pregnant women ( P = 0.291), respectively. No statically significant differences in the FasL-844 genotype were observed between the groups ( P = 0.69). Conclusion The Fas-1377G > A polymorphism is associated with a higher risk of pre-eclampsia. [ABSTRACT FROM AUTHOR]

Background: A novel member of the interleukin (IL)-12 family, IL-35 is an important inhibitory cytokine released by regulatory T cells. The aim of this study is to evaluate gingival crevicular fluid (GCF), saliva, and plasma levels of IL-35 in periodontal disease and health. Methods: Samples of GCF, whole saliva, and plasma were obtained from systemically healthy, non-smoking individuals with gingivitis (n = 20) or chronic periodontitis (CP) (n = 20) and periodontally healthy individuals (n = 20). Full-mouth clinical periodontal measurements, including probing depth (PD), bleeding on probing, gingival index, and plaque index (PI), were also recorded. Enzyme-linked immunosorbent assay was used to determine IL-35 levels in the samples. Data were tested statistically by analysis of variance and Pearson rank correlation test. Results: All clinical parameters were significantly higher in the CP group than the healthy and gingivitis groups (P<0.001). The GCF total amount of IL-35 was significantly higher in the CP group than the other groups (P = 0.04), whereas the GCF concentration of IL-35 was significantly higher in the healthy group than the other groups (P -0.002). There were significant differences among the study groups in terms of salivary IL-35 level (P<0.001), with the highest level observed in the healthy group and the lowest in the CP group. There was no statistical difference between groups in plasma levels of IL-35 (P>0.05). There was a positive correlation between GCF total amount of IL-35 and PD (r= 0.338, P= 0.03) and PI (r= 0.374, P= 0.005) parameters. Conclusions: IL-35 could have an important role in suppressing periodontal inflammation and maintaining periodontal health. Additional studies are required to evaluate its role in periodontal diseases. [ABSTRACT FROM AUTHOR]

Glucocorticoids ( GCs) are released from the adrenal gland during inflammation and help to keep immune responses at bay. Owing to their potent anti-inflammatory activity, GCs also play a key role in controlling acute graft-versus-host disease ( aGvHD). Here we demonstrate that mice lacking the glucocorticoid receptor ( GR) in T cells develop fulminant disease after allogeneic bone marrow transplantation. In a fully MHC-mismatched model, transfer of GR-deficient T cells resulted in severe aGvHD symptoms and strongly decreased survival times. Histopathological features were aggravated and infiltration of CD8+ T cells into the jejunum was increased when the GR was not expressed. Furthermore, serum levels of IL-2, IFNγ, and IL-17 were elevated and the cytotoxicity of CD8+ T cells was enhanced after transfer of GR-deficient T cells. Short-term treatment with dexamethasone reduced cytokine secretion but neither impacted disease severity nor the CTLs' cytolytic capacity. Importantly, in an aGvHD model in which disease development exclusively depends on the presence of CD8+ T cells in the transplant, transfer of GR-deficient T cells aggravated clinical symptoms and reduced survival times as well. Taken together, our findings highlight that suppression of CD8+ T-cell function is a crucial mechanism in the control of aGvHD by endogenous GCs. Copyright © 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

This article presents scientific background information on the animated 3D film ' Inflammatory Reactions - Communication of Cells' ( Quintessence Publications, ISBN 978-1-85097-231-0). Gingivitis and periodontitis are understood as the result of a coordinated action of a few clearly identified cellular players who communicate with each other via cytokines. For didactic reasons, the course of a periodontal infection is described here in four phases: (1) bacterial biofilm formation and development of a host response in the marginal periodontium, (2) innate immune response leading to gingivitis, (3) role of the adaptive immune system in attachment loss and pocket formation, and (4) down-regulation of inflammation and periodontal regeneration and repair following biofilm removal. The control of the cells is discussed as a cytokine network, which can be modulated in pro- or anti-inflammatory direction depending on the control of the bacterial infection. Degradation of soft tissue structural proteins like collagen and proteoglycans by matrix metalloproteinases and degradation of hard tissue matrix by osteoclasts are explained as an interference of the immune system with the natural equilibrium of tissue remodeling. Five mechanisms of promotion of bone loss through the influence of the immune system are described. One example is bone resorption as a consequence of the shift of the RANKL/osteoprotegerin balance by soluble RANKL synthesized by CD4+ Th1 cells as well as the interference with the coupling of osteoclasts and osteoblasts through dedifferentiation of osteoblasts by TNFα. Finally, the signaling required for down-regulation of inflammatory reactions and the reasons for the incomplete regeneration after periodontal bone loss are discussed. [ABSTRACT FROM AUTHOR]

Several studies have documented that dietary modifications influence the development of type 1 diabetes. However, little is known about the interplay of dietary components and the penetration of diabetes incidence. In this study we tested if wheat gluten is able to induce differences in the cytokine pattern of Foxp3+ regulatory T cells, as well as Foxp3− T cells, isolated from intestinal mucosal lymphoid tissue and non-mucosal lymphoid compartments in BALB/c mice. The gluten-containing standard diet markedly changed the cytokine expression within Foxp3− T cells, in all lymphoid organs tested, towards a higher expression of pro-inflammatory interferon-γ ( IFN-γ), interleukin-17 ( IL-17) and IL-2. In Foxp3+ regulatory T cells, gluten ingestion resulted in a mucosal increase in IL-17 and IL-2 and an overall increase in IFN-γ and IL-4. The gluten-free diet induced an anti-inflammatory cytokine profile with higher proportion of transforming growth factor-β ( TGF-β)+ Foxp3− T cells in all tested lymphoid tissues and higher IL-10 expression within non-T cells in spleen, and a tendency towards a mucosal increase in TGF-β+ Foxp3+ regulatory T cells. Our data shows that the gluten-containing standard diet modifies the cytokine pattern of both Foxp3− T cells and Foxp3+ regulatory T cells towards a more inflammatory cytokine profile. This immune profile may contribute to the higher type 1 diabetes incidence associated with gluten intake. [ABSTRACT FROM AUTHOR]

Invariant NKT (iNKT) cells are a distinctive subtype of CD1d-restricted T cells involved in regulating autoimmunity and capable of producing various T helper type 1 (Th1), Th2 and Th17 cytokines. Activation of iNKT cells by their exogenous ligand α-galactosylceramide (α-GalCer) exerts therapeutic effects in autoimmune diseases such as rheumatoid arthritis (RA). However, the pathophysiological role of iNKT cells in RA, in the absence of exogenous stimulation, is incompletely understood. We investigated the potential pathophysiological effects of iNKT cells in mice with collagen-induced arthritis (CIA), a model of RA. We found that iNKT cells underwent activation only in the early phases of the disease (6 days post-induction). In the liver, but not the spleen or lymph nodes, this early activation led to the release of interleukins -4, -17A and -10 and of interferon-γ; and an increased CD69 expression. Importantly, clinical and histological signs of arthritis were improved by the functional blockade of iNKT cells by a monoclonal antibody to CD1d at the early phase of the disease. This improvement was associated on day 6 post-induction with decreased expression of co-stimulatory molecules (CD80, CD86, CD40) on splenic dendritic cells and macrophages, whereas regulatory T-cell suppressive effects and proportions were not modified. Taken in concert, these findings suggest that iNKT cells are activated early in the course of CIA and contribute to the pathogenesis of arthritis. Therefore, iNKT-cell activation may be a valid treatment target in RA. [ABSTRACT FROM AUTHOR]

Autoinflammatory syndromes include an expanding list of conditions characterized by unprovoked recurrent attacks of systemic inflammation with lack of auto-antibodies or autoreactive T cells. Many of these syndromes are genetic diseases with a Mendelian inheritance. Neurological manifestations may be one of the major clinical features and, in some cases, the presenting symptom of these syndromes. The purpose of this review is to increase the recognition among neurologists of the Mendelian-inherited autoinflammatory syndromes by highlighting the neurological manifestations in the context of other symptoms that should lead physicians to suspect these syndromes. Most important for neurologists are the cryopyrin-associated periodic syndromes that include familial cold autoinflammatory syndrome, Muckle–Wells syndrome and neonatal-onset multisystem inflammatory disease (called chronic infantile neurological cutaneous and articular syndrome in Europe). We also review other syndromes with less common neurological involvement, including familial Mediterranean fever, tumor necrosis factor receptor-associated periodic syndrome, and hyperimmunoglobulinemia D syndrome. Because these syndromes are often treatable and irreversible damage is prevented if they are treated early, it is important to recognize the features that may result in these syndromes presenting to a neurologist, especially in early childhood. [ABSTRACT FROM AUTHOR]

Background and Purpose: Allergic inflammation and autoimmune diseases, such as atopic dermatitis, psoriasis and multiple sclerosis (MS), involve both mast cell and T-cell activation. However, possible interactions between the two and the mechanism of such activations are largely unknown.Experimental Approach: Human umbilical cord blood-derived cultured mast cells (hCBMCs) and Jurkat T cells were incubated separately or together, following activation with myelin basic protein (MBP), as well as with or without pretreatment with the flavonoid luteolin for 15 min. The supernatant fluid was assayed for inflammatory mediators released from mast cells and interleukin (IL)-2 release from Jurkat cells.Key Results: MBP (10 microM) stimulates hCBMCs to release IL-6, IL-8, transforming growth factor (TGF)-beta1, tumour necrosis factor-alpha (TNF-alpha), vascular endothelial growth factor (VEGF), histamine and tryptase (n=6, P<0.05). Addition of mast cells to Jurkat cells activated by anti-CD3/anti-CD28 increases IL-2 release by 30-fold (n=3, P<0.05). MBP-stimulated mast cells and their supernatant fluid further increase Jurkat cell IL-2 release (n=3, P<0.05). Separation of mast cells and activated Jurkat cells by a Transwell permeable membrane inhibits Jurkat cell stimulation by 60%. Pretreatment of Jurkat cells with a TNF-neutralizing antibody reduces IL-2 release by another 40%. Luteolin pretreatment inhibits mast cell activation (n=3-6, P<0.05), Jurkat cell activation and mast cell-dependent Jurkat cell stimulation (n=3, P<0.05).Conclusions and Implications: Mast cells can stimulate activated Jurkat cells. This interaction is inhibited by luteolin, suggesting that this flavonoid may be useful in the treatment of autoimmune diseases. [ABSTRACT FROM AUTHOR]

The article discusses several studies on the role of T lymphocytes in rheumatoid arthritis (RA) and other autoimmune diseases. A 1976 study was able to determine the predominance of T cells in lymphocytic infiltrates in RA patients by using antibodies and immunofluorescence. Another study demonstrated that T lymphocytes affect the activity of inflammation in RA. A model was developed to distinguish subsets of CD4+ effector T cells based on cytokine production.

Heme oxygenase-1 (HO-1) is increased in psoriatic skin. We asked for the impact of physiological and pharmacological HO-1 induction on skin immunity and the mechanisms involved in HO-1-induced immunomodulation. We found cutaneous HO-1 expression upregulated comparable with suppressors of cytokine signalling (SOCS)1 and SOCS3 in psoriasis and atopic eczema and temporarily increased in murine ovalbumin-induced late phase reaction (LPR) and 2,4-dinitrofluorobenzene (DNFB)-induced contact hypersensitivity (CHS). Cutaneous inflammation was enhanced by HO-1 inhibition and was abrogated by treatment with the HO-1 inducer cobaltic protoporphyrin (CoPP) both when applied around sensitization or before challenge. HO-1 inhibition specifically prevented the anti-inflammatory CoPP effect. CoPP inhibited T cell proliferation in splenocytes of treated mice and in human mixed leukocyte reaction and lymphocyte transformation test. CoPP induced HO-1 in antigen-presenting cells and depressed monocytic accessory molecule expression and the differentiation and maturation of monocyte-derived dendritic cells (MDDC). It decreased tumor necrosis factor (TNF)-α and interleukin (IL)-12 production while increasing IL-10 secretion. The antigen-presenting capacity was diminished in CoPP-treated and HO-1-transduced MDDC. We demonstrate for the first time the physiological role of HO-1 in the limitation of skin inflammation and implement pharmacological HO-1 induction as a therapeutic approach for T cell-dependent inflammatory dermatoses. Suppression of antigen-presenting cells may represent a main anti-inflammatory mechanism of HO-1. [ABSTRACT FROM AUTHOR]

Suppressor of cytokine signalling-1 (SOCS1), as the name implies, is a protein that functions as a negative regulator of cytokine signalling. Initially characterized for its ability to inhibit JAK phosphorylation and function, SOCS1 also targets proteins for degradation by the proteosome machinery. The expression of SOCS1 can be regulated at the transcription, translation and protein level. Despite the broad spectrum of cytokines that can induce SOCS1 expression and/or be inhibited by SOCS1 in vitro, the use of genetically modified mice has revealed a more specific role for SOCS1 in vivo including a critical role in the regulation of IFNγ signalling. In addition, SOCS1 has a complex role in T cell activation, and studies have revealed significant roles for SOCS1 in the regulation of IL-4, IL-12 and IL-15 in vivo. Interestingly, SOCS1 action is not limited to the regulation of the classical JAK/STAT-signalling pathway, because SOCS1 also inhibits cytokines like insulin and toll-like receptor signal transduction, neither of which activates the JAK/STAT pathway. Evidence is emerging for a role for aberrant SOCS1 expression in human disease, particularly in a number of malignancies. [ABSTRACT FROM AUTHOR]