use prefix []or [-]not [+]and [=]has feature [!]exclude feature ie. 'interleukin-6 -animal +phenotypic =protein !tumor'

Displaying 8 papers, 1 pages, start at 1, 8 Hits
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IL-6 and IL-27

Despite the apparent protective role of IL-6, high levels of IL-6 in serum or cerebrospinal fluid have been reported in severe neurologically complicated IAV cases, with IL-6 used as a marker for prognosis (199-201, 209, 210) . The role of IL-6 in regulation of BBB permeability was reported (211) , with potentially detrimental neurological complications. As such, the suppression of hyper-induced IL-6 as a form of therapy in severe IAV infection should be considered. One such option is the anti-IL6 antibodybased drug tocilizumab, which is currently administered clinically for the treatment of rheumatoid arthritis. However, study on the usage of this drug to treat hyper upregulation of IL-6 due to severe IAV infection has yet to be conducted. On the other hand, in a case of H1N1 virus-induced ARDS, the use of an extracorporeal cytokine hemoadsorption device to remove cytokines including TNF and IL-6 from the bloodstream (212) has showed beneficial to the patient (213) . More research is required to confirm whether the removal or neutralization of IL-6 could be a potential therapy for severe IAV infections.
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Blockade of TnFα, But not il-17, iFnγ, il-6r, or cD80/cD86-Mediated costimulation, regulates il-10 in human cD4 + T cells Our previous work demonstrated that in addition to adalimumab, other TNFα inhibitors (etanercept, infliximab, or certolizumab) as well as TNFR1/2 blocking mAbs were capable of increasing frequencies of IL-10-expressing IL-17 + CD4 + T cells (20) . We investigated whether blockade of additional pro-inflammatory pathways could promote IL-10 expression in CD4 + T cells. Blockade of IL-17A did not enhance the frequencies of IL-10 + cells in any of the CD4 + T cell populations tested (Figure 4A) . Blockade of IFNγ did not affect the percentage of IL-10 + cells within total CD4 + T cells, or within IFNγ or TNFα + subpopulations, but led to modestly increased frequencies of IL-10 + expressing cells within the IL-17 + population, although this effect was much weaker than the effect of TNF blockade in parallel cultures ( Figure 4A) . Addition of tocilizumab (IL-6R blockade) or abatacept (CTLA4-Ig, which blocks CD80/CD86-mediated co-stimulation), both of which are biologic drugs routinely used in the clinic to treat rheumatoid arthritis, did not increase IL-10 + frequencies in CD4 + T cells, IL-17 + , IFNγ + , or TNFα + CD4 + T cell subpopulations (Figure 4B) . To determine whether blockade of these pathways might regulate IL-10 expression with different kinetics to TNF blockade, IL-10 + frequencies were analyzed within both CD4 + and CD8 + T cells at different time points in anti-CD3-stimulated PBMC cultures exposed to these antibodies or drugs. IL-10 + CD4 + and IL-10 + CD8 + T cell frequencies were not regulated at any time point by blockade of IL-17, IFNγ, IL-6R, or CD80/CD86-mediated co-stimulation ( Figure S5 in Supplementary Material). Blockade of IL-1R1 in CD4 + T cell/monocyte cocultures resulted in a significantly increased proportion of IL-10 + cells within total CD4 + T cells and within IL-17 + , IFNγ + , or TNFα + subpopulations ( Figure 4B) . However, this effect was not replicated in either CD4 + or CD8 + T cells in whole PBMC cultures ( Figure S5 in Supplementary Material), indicating that the capacity of IL-1 blockade to regulate IL-10 expression may be dependent on the in vitro culture conditions. Together these data indicate that IL-10 expression in CD4 + T cells and CD8 + T cells can be regulated by blocking TNFα signaling, but not by blocking IFNγ, IL-17, IL-6R, or CD80/CD86-mediated co-stimulation, at least in vitro.
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We further proved that IgG-producing PBs in the CSF during relapse share identical CDR sequences with those from PBs in the peripheral blood ( Table 2 ). The IgG sequences were highly mutated ( Figure S4 and S5) , indicating that helper T-cells guided the PBs toward germinal centers. Although we did not separate CD138 − and CD138 + PBs in this analysis, the number of mutations in the H-chain variable regions showed a singlepeak distribution (Figure S4) . These results suggest that both CD138 − and CD138 + PBs are affinity-maturated B-cells, although CD138 expression levels could inversely correlate with the tissue-migrating ability [23] . There remained a possibility that mB might give rise to PBs within the CSF. However, further affinity maturation in PBs was not observed in CSF compared with peripheral blood, indicating that clonal expansion and differentiation of mB in the CSF is not a major pathway. This assumption is also supported by the rare occurrence of CSF oligoclonal bands and raised IgG index in NMO, which indicates that the intrathecal IgG synthesis was low, transient, and restricted to acute relapse in NMO patients [6, 31] . Taken together, it is likely that CXCR3-expressing PBs are expanded in the periphery and recruited to the CNS in the pathogenesis of NMO. In the CNS, B-cell stimulatory cytokines such as IL-6 would support the PB survival and AQP4-Ab production, leading to the destruction of astrocytes and the glia limitans. We and another group have shown that PBs from peripheral blood and CSF produce anti-AQP4 IgG antibody in NMO [10, 12] . We therefore postulated that the common IgGs shared by PBs from the PBMC and CSF (Table 2 ) could bind to AQP4. Despite substantial efforts, however, we have not succeeded in this attempt so far. Though we speculate that peripherally expanded PBs producing anti-AQP4 should be able to cross BBB like other PBs, irrespective of the antigen specificity, more efforts will be needed to formally prove our postulate. We previously demonstrated the role of IL-6-dependent PBs in the production of AQP4-Ab [12] . In the present report, we indicate that PBs may play a more critical role in the CNS by locally producing AQP4-Ab. The relevance of this model can be verified in clinical trials of drugs targeting appropriate cells or molecules. In fact, we have recently shown that humanized anti-IL-6 receptor antibody (Tocilizumab) was efficacious in a patient with NMO in reducing the number of PBs in the peripheral blood as well as stabilizing the clinical conditions [32] . In another report, Tocilizumab successfully controlled three NMO patients who were resistant to the anti-CD20 antibody Rituximab [33] . These results indicate that PBs, rather than CD20 + mB, play a pivotal role in NMO. Therefore, it will be intriguing to test the effect of drugs altering the migration of PBs toward the CNS [34] . Figure S1 . Flow cytometric analysis of PB. Flow cytometric scheme of B-cell subpopulation analysis. The partitioned cells are CD19 + CD27 + cells within peripheral blood mononuclear cells (PBMC; left panel). The CD19 + CD27 + cells were further analyzed to investigate the expression of CD38 and CD180 (middle panel). CD38 high CD180 -cells (partitioned in the middle panel), corresponding to plasmablast (PB) cells, were analyzed again to investigate the expression of CD19 and CD27 (right panel). This result assured that the encircled population in Figure 1A represented CD19 int CD27 high CD38 high CD180 -PB cells.
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An important limitation of this study is that IL-6 and IL-10 are unlikely to constitute the only two cytokines driving the STAT3-PD-L1 pathway, and we expect that there is redundancy in which cytokine drives PD-L1, as long as STAT3 is adequately activated. STAT3 can also be activated by nearly 20 members of the IL-6 and IL-10 cytokine families. However, IL-6 and IL-10 are two of the most abundant cytokines secreted by myeloid cells upon activation, and while dual blockade of the receptors led to a ~45% reduction in PD-L1, this could reflect the fact that blocking antibodies do not completely neutralise all biological activity 33 . STAT3 can also be weakly activated by TLR signalling and Src-family kinases 34,35 , and we cannot exclude the possibility of such contributions to its phosphorylation state. Furthermore, there are undoubtedly other transcriptional co-factors recruited to the Cd274 promoter alongside STAT3. Regardless, we have conclusively shown that STAT3 is biologically essential for its activity by BCG, and linked this to biological targets that are amenable to intervention in clinical settings (e.g. tocilizumab, an α-IL-6R mAb). Indeed, this study provides four such points of intervention when using BCG: (i)