Psykiatrian palvelut tulevat kotiin

Liikkuvilla palveluilla pyritään tulevaisuudessa monipuolistamaan myös psykiatrian lähipalveluja. Satakunnan sairaanhoitopiirissä työmuoto on tuttu etenkin lastenpsykiatrian puolella. Toiminta edellyttää hyvää suunnittelua ja koordinointia

CD4+FoxP3+ regulatory T cells confer infectious tolerance in a TGF-β–dependent manner

CD4+FoxP3+ regulatory T (T reg) cells comprise a separate lineage of T cells that are essential for maintaining immunological tolerance to self. The molecular mechanism(s) by which T reg cells mediate their suppressive effects remains poorly understood. One molecule that has been extensively studied in T reg cell suppression is transforming growth factor (TGF)-β, but its importance remains controversial. We found that TGF-β complexed to latency-associated peptide (LAP) is expressed on the cell surface of activated but not resting T reg cells. T reg cell LAP–TGF-β plays an important role in the suppression of the proliferation of activated T cells, but it is not required for the suppression of naive T cell activation. More importantly, T reg cell–derived TGF-β could generate de novo CD4+FoxP3+ T cells in vitro from naive precursors in a cell contact–dependent, antigen-presenting cell–independent and αV integrin–independent manner. The newly induced CD4+FoxP3+ T cells are suppressive both in vitro and in vivo. Transfer of activated antigen-specific T reg cells with naive antigen-specific responder T cells to normal recipients, followed by immunization, also results in induction of FoxP3 expression in the responder cells. T reg cell–mediated generation of functional CD4+FoxP3+ cells via this TGF-β–dependent pathway may represent a major mechanism as to how T reg cells maintain tolerance and expand their suppressive abilities

Interaction of STAT6 with its co-activator SRC-1/NCoA-1 is regulated by dephosphorylation of the latter via PP2A

Regulation of gene expression represents a central issue in signal-regulated cellular responses. STAT6 is a critical mediator of IL-4 stimulated gene activation. To mediate this function, STAT6 recruits co-activator complexes. We have previously shown that STAT6 binds the PAS-B domain of the co-activator NCoA-1 via an LXXLL motif in its transactivation domain. Our recent finding that the PAS-B domain of NCoA-1 is also essential for co-activator complex formation points to an additional level of regulation of the co-activator assembly. In this study, we discovered that dephosphorylation of NCoA-1 is essential for the interaction with STAT6 and for IL-4-dependent transcriptional activation. PP2A dephosphorylates NCoA-1 and facilitates the activation of STAT6 target genes. Interestingly, simultaneous inhibition of phosphatase and cyclin-dependent kinases rescues the NCoA-1/STAT6 interaction. Moreover, arrest of cells at G1/S results in enhanced NCoA-1 phosphorylation. In summary, our results indicate that the interaction of NCoA-1 and STAT6 is dynamically regulated by the phosphatase PP2A and by cyclin-dependent kinases. This provides a mechanism for integrating transcriptional regulation by STAT6 with cell cycle progression

In Vitro Functional and Immunomodulatory Properties of the Lactobacillus helveticus MIMLh5-Streptococcus salivarius ST3 Association That Are Relevant to the Development of a Pharyngeal Probiotic Product

The use of proper bacterial strains as probiotics for the pharyngeal mucosa is a potential prophylactic strategy for upper respiratory tract infections. In this context, we characterized in vitro the functional and immunomodulatory properties of the strains Lactobacillus helveticus MIMLh5 and Streptococcus salivarius ST3 that were selected during previous investigations as promising pharyngeal probiotics. In this study, we demonstrated in vitro that strains MIMLh5 and ST3, alone and in combination, can efficiently adhere to pharyngeal epithelial cells, antagonize Streptococcus pyogenes, and modulate host innate immunity by inducing potentially protective effects. In particular, we found that the strains MIMLh5 and ST3 activate U937 human macrophages by significantly inducing the expression of the proinflammatory cytokine tumor necrosis factor alpha (TNF-\u3b1). Nonetheless, the induction of the anti-inflammatory interleukin-10 (IL-10) by MIMLh5 or ST3 was never lower than that of TNF-\u3b1, suggesting that these bacteria can potentially exert a regulatory rather than a proinflammatory effect. We also found that the strains MIMLh5 and ST3 induce cyclooxygenase 2 (COX-2) expression and demonstrated that toll-like receptor 2 (TLR-2) participates in the recognition of the strains MIMLh5 and ST3 by U937 cells. Finally, we observed that these microorganisms grow efficiently when cocultured in milk, suggesting that the preparation of a milk-based fermented product containing both MIMLh5 and ST3 can be a practical solution for the administration of these bacteria. In conclusion, we propose the combined use of L. helveticus MIMLh5 and S. salivarius ST3 for the preparation of novel products that display probiotic properties for the pharyngeal mucosa

STAT6 and Furin Are Successive Triggers for the Production of TGF-β by T Cells

Production of TGF-β by T cells is key to various aspects of immune homeostasis, with defects in this process causing or aggravating immune-mediated disorders. The molecular mechanisms that lead to TGF-β generation by T cells remain largely unknown. To address this issue, we take advantage of the fact that intestinal helminths stimulate Th2 cells besides triggering TGF-β generation by T lymphocytes and regulate immune-mediated disorders. We show that the Th2 cell-inducing transcription factor STAT6 is necessary and sufficient for the expression of TGF-β propeptide in T cells. STAT6 is also necessary for several helminth-triggered events in mice, such as TGF-β-dependent suppression of alloreactive inflammation in graft-versus-host disease. Besides STAT6, helminth-induced secretion of active TGF-β requires cleavage of propeptide by the endopeptidase furin. Thus, for the immune regulatory pathway necessary for TGF-β production by T cells, our results support a two-step model, composed of STAT6 and furin

Tpl2 kinase regulates T cell interferon-γ production and host resistance to Toxoplasma gondii

Tpl2 (Tumor progression locus 2), also known as Cot/MAP3K8, is a hematopoietically expressed serine-threonine kinase. Tpl2 is known to have critical functions in innate immunity in regulating tumor necrosis factor–α, Toll-like receptor, and G protein–coupled receptor signaling; however, our understanding of its physiological role in T cells is limited. We investigated the potential roles of Tpl2 in T cells and found that it was induced by interleukin-12 in human and mouse T cells in a Stat4-dependent manner. Deficiency of Tpl2 was associated with impaired interferon (IFN)-γ production. Accordingly, Tpl2−/− mice had impaired host defense against Toxoplasma gondii with reduced parasite clearance and decreased IFN-γ production. Furthermore, reconstitution of Rag2−/− mice with Tpl2-deficient T cells followed by T. gondii infection recapitulated the IFN-γ defect seen in the Tpl2-deficient mice, confirming a T cell–intrinsic defect. CD4+ T cells isolated from Tpl2−/− mice showed poor induction of T-bet and failure to up-regulate Stat4 protein, which is associated with impaired TCR-dependent extracellular signal-regulated kinase activation. These data underscore the role of Tpl2 as a regulator of T helper cell lineage decisions and demonstrate that Tpl2 has an important functional role in the regulation of Th1 responses

Future therapeutic targets in rheumatoid arthritis?

Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by persistent joint inflammation. Without adequate treatment, patients with RA will develop joint deformity and progressive functional impairment. With the implementation of treat-to-target strategies and availability of biologic therapies, the outcomes for patients with RA have significantly improved. However, the unmet need in the treatment of RA remains high as some patients do not respond sufficiently to the currently available agents, remission is not always achieved and refractory disease is not uncommon. With better understanding of the pathophysiology of RA, new therapeutic approaches are emerging. Apart from more selective Janus kinase inhibition, there is a great interest in the granulocyte macrophage-colony stimulating factor pathway, Bruton's tyrosine kinase pathway, phosphoinositide-3-kinase pathway, neural stimulation and dendritic cell-based therapeutics. In this review, we will discuss the therapeutic potential of these novel approaches

Myeloid cell expressed proprotein convertase FURIN attenuates inflammation

The proprotein convertase enzyme FURIN processes immature pro-proteins into functional end- products. FURIN is upregulated in activated immune cells and it regulates T-cell dependent peripheral tolerance and the Th1/Th2 balance. FURIN also promotes the infectivity of pathogens by activating bacterial toxins and by processing viral proteins. Here, we evaluated the role of FURIN in LysM+ myeloid cells in vivo. Mice with a conditional deletion of FURIN in their myeloid cells (LysMCre-fur(fl/fl)) were healthy and showed unchanged proportions of neutrophils and macrophages. Instead, LysMCre-fur(fl/fl) mice had elevated serum IL-1\u3b2 levels and reduced numbers of splenocytes. An LPS injection resulted in accelerated mortality, elevated serum proinflammatory cytokines and upregulated numbers of pro-inflammatory macrophages. A genome-wide gene expression analysis revealed the overexpression of several pro-inflammatory genes in resting FURIN-deficient macrophages. Moreover, FURIN inhibited Nos2 and promoted the expression of Arg1, which implies that FURIN regulates the M1/M2-type macrophage balance. FURIN was required for the normal production of the bioactive TGF-\u3b21 cytokine, but it inhibited the maturation of the inflammation-provoking TACE and Caspase-1 enzymes. In conclusion, FURIN has an anti-inflammatory function in LysM+ myeloid cells in vivo

A Novel Requirement for Janus Kinases as Mediators of Drug Resistance Induced by Fibroblast Growth Factor-2 in Human Cancer Cells

The development of resistance to chemotherapy is a major cause of cancer-related death. Elucidating the mechanisms of drug resistance should thus lead to novel therapeutic strategies. Fibroblast growth factor (FGF)-2 signaling induces the assembly of a multi-protein complex that provides tumor cells with the molecular machinery necessary for drug resistance. This complex, which involves protein kinase C (PKC) ε, v-raf murine sarcoma viral oncogene homolog B1 (B-RAF) and p70 S6 kinase β (S6K2), enhances the selective translation of anti-apoptotic proteins such as B-cell leukaemia/lymphoma-2 (BCL-2) and inhibitors of apoptosis protein (IAP) family members and these are able to protect multiple cancer cell types from chemotherapy-induced cell death. The Janus kinases (JAKs) are most noted for their critical roles in mediating cytokine signaling and immune responses. Here, we show that JAKs have novel functions that support their consideration as new targets in therapies aimed at reducing drug resistance. As an example, we show that the Janus kinase TYK2 is phosphorylated downstream of FGF-2 signaling and required for the full phosphorylation of extracellular signal-regulated kinase (ERK) 1/2. Moreover, TYK2 is necessary for the induction of key anti-apoptotic proteins, such as BCL-2 and myeloid cell leukemia sequence (MCL) 1, and for the promotion of cell survival upon FGF-2. Silencing JAK1, JAK2 or TYK2 using RNA interference (RNAi) inhibits FGF2-mediated proliferation and results in the sensitization of tumor cells to chemotherapy-induced killing. These effects are independent of activation of signal transducer and activator of transcription (STAT) 1, STAT3 and STAT5A/B, the normal targets of JAK signaling. Instead, TYK2 associates with the other kinases previously implicated in FGF-2-mediated drug resistance. In light of these findings we hypothesize that TYK2 and other JAKs are important modulators of FGF-2-driven cell survival and that inhibitors of these kinases will likely improve the effectiveness of other cancer therapies

High Frequency of CD4+CXCR5+ TFH Cells in Patients with Immune-Active Chronic Hepatitis B

BACKGROUND: T follicular helper (TFH) cells are a special subpopulation of T helper cells and can regulate humoral immune responses. This study examined whether the frequency of CD4(+)CXCR5(+) TFH cells could be associated with active immunity in chronic hepatitis B (CHB) patients. METHODOLOGY AND FINDINGS: The frequencies of peripheral blood CD4(+)CXCR5(+) TFH cells, inducible T cell costimulator (ICOS), and/or programmed death 1 (PD-1) positive CD4(+)CXCR5(+) TFH cells in immune-active (IA), immune-tolerant (IT) CHB, and healthy controls (HC) were characterized by flow cytometry analysis. The effect of adevofir dipivoxil treatment on the frequency of CD4(+)CXCR5(+) TFH cells, the concentrations of serum IL-2, IFN-γ, TNF-α, IL-4, IL-6, IL-10, IL-21, ALT, AST, HBsAg, HBsAb, HBeAg, HBeAb and HBV loads in IA patients were determined. The potential association of the frequency of CD4(+)CXCR5(+) TFH cells with clinical measures was analyzed. In addition, the frequency of splenic and liver CD4(+)CXCR5(+) TFH cells in HBV-transgenic mice was examined. We found that the frequency of CD4(+)CXCR5(+) TFH cells in IA patients was significantly higher than that of IT patients and HC, and the percentages of CD4(+)CXCR5(+) TFH in IA patients were positively correlated with AST. Furthermore, the percentages of ICOS(+), PD-1(+), and ICOS(+)PD-1(+) in CD4(+)CXCR5(+) TFH cells in CHB patients were significantly higher than that of HC. Treatment with adefovir dipivoxil reduced the frequency of CD4(+)CXCR5(+) TFH, PD-1(+)CD4(+)CXCR5(+) TFH cells and the concentrations of HBsAg and HBeAg, but increased the concentrations of HBsAb, HBeAb, IL-2 and IFN-γ in IA patients. Moreover, the frequency of splenic and liver CD4(+)CXCR5(+) TFH cells in HBV-transgenic mice was higher than that of wild-type controls. CONCLUSIONS: These data indicate that CD4(+)CXCR5(+) TFH cells may participate in the HBV-related immune responses and that high frequency of CD4(+)CXCR5(+) TFH cells may be a biomarker for the evaluation of active immune stage of CHB patients