Calcium and its major downstream effector, calcium/calmodulin-dependent protein kinase II (CaMKII), are found to be important for the functions of immune cells. Lipopolysaccharide (LPS) has been shown to induce intracellular calcium release in macrophages; however, whether and how CaMKII is required for Toll-like receptor (TLR) signaling remain unknown. Here we demonstrate that TLR 4, 9, and 3 ligands markedly induce intracellular calcium fluxes and activate CaMKII-␣ in macrophages. Selective inhibition or RNA interference of CaMKII significantly suppresses TLR4, 9, 3-triggered production of interleukin-6 (IL-6), tumor necrosis factor-␣, and interferon-␣/ (IFN-␣/) in macrophages. Coincidently, overexpression of constitutively active CaMKII-␣ significantly enhances production of the above cytokines. In addition to the activation of mitogen-activated protein kinase and nuclear factor B pathways, CaMKII-␣ can directly bind and phosphorylate transforming growth factor -activated kinase 1 (TAK1) and IFN regulatory factor 3 (IRF3; serine IntroductionOn recognition of pathogenic components, Toll-like receptors (TLRs) are activated, leading to a variety of signaling events that initiate innate immunity and activate immune cells to produce proinflammatory cytokines and type I interferon (IFN). 1,2 Most of the members of the TLR family, with the exception of TLR3, trigger immune response via the conserved myeloid differentiation factor 88 (MyD88)-dependent pathway, which involves MyD88, interleukin-1 (IL-1) receptor-associated kinase 1 (IRAK1), tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6), transforming growth factor- (TGF-)-activated kinase 1 (TAK1), downstream mitogen-activated protein kinases (MAPKs), and nuclear factor B (NF-B). 2,3 Toll/IL-1 receptor-domain-containing adaptor protein inducing IFN- (TRIF) has been found to induce the expression of type I IFN in response to TLR4 and TLR3 ligands, which associates with TANK-binding kinase 1 (TBK1) and activates downstream IFN regulatory factor 3 (IRF3). In addition, the TRIF pathway also contributes to TLR3-and TLR4-activated proinflammatory cytokine production. 3,4 TLR activation is essential for provoking the innate immune response and enhancing adaptive immunity against invading pathogens. Less efficient activation of the TLR response may not evoke potent anti-infection or antitumor immunity; however, excessive activation of TLR may also induce immunopathologic processes, such as endotoxin shock and autoimmune diseases. How to manipulate or control the TLR response for prevention and treatment of inflammatory and immunologic diseases largely depends on the understanding of the molecular basis for TLR responses. Up to now, molecular mechanisms for the initiation and regulation of TLR responses remain to be fully understood. In addition to the MyD88-or TRIF-dependent pathway, ligation of TLRs has been found to activate various other intracellular signaling molecules, such as phosphatidylinositol 3-kinase (PI3K)/ AKT 5 and MAPK kinase kinase (ME...
BackgroundIt has been previously reported that IL-22, one of the cytokines secreted by Th17 cells, demonstrates both a protective and inflammatory promotion effect in inflammatory bowel disease (IBD) through STAT3 signaling activation. We sought to investigate the role of IL-22 expression in colon cancer (CC).MethodsThe expression of IL-22 and related molecules were detected in human CC, the detail function and mechanism of IL-22 were investigated by in vivo and in vitro model.ResultsOur results demonstrated significant upregulation of IL-22 in human CC tumor infiltrated leukocytes (TILs) compared to peripheral lymphocytes. Moreover, our findings demonstrated that IL-22 expression was significantly higher in ulcerative colitis (UC) tissues versus normal colon tissues. Both IL-22 receptor α1 (IL-22RA1) and IL-23 were highly expressed in CC and UC tissues compared to normal controls. TILs exhibiting various IL-22 expression levels isolated from CC patients were demonstrated to enhance tumor growth and metastasis co-transplanted with Hct-116 cells underwent subcutaneous transplantation in mice model. Tumor growth and metastasis was promoted by STAT3 phosphorylation and upregulation of its downstream genes such as Bcl-xl, CyclinD1, and VEGF. In vitro studies confirmed the anti-apoptotic and pro-proliferation effect of IL-22 according to the BrdU cooperation assay and peroxide induced apoptosis analysis with or without the presence of IL-22.ConclusionIn this study we demonstrated that excessive IL-22 in the CC and UC microenvironment leads to tumor growth, inhibition of apoptosis, and promotion of metastasis depend on STAT3 activation.
The median (interquartile range) age of the patients was 35 (24-50) years. A total of 8 patients (89%) reported fever (mean [SD] duration, 5.78 [2.99] days), and 7 patients (78%) reported a cough. Few patients (3 [33%]) showed debilitation, chest distress (2 [22%]), or anorexia (1 [11%]). Diarrhea, myalgia, rhinorrhea, and headache were not reported. C-reactive protein levels were elevated in 9 patients (100%; mean [SD], 3.34 [3.18] mg/dL; to convert to milligrams per liter, multiply by 10).Lymphopenia occurred in 3 patients (33%), lactate dehydrogenase was increased in 3 patients (33%;Author affiliations and article information are listed at the end of this article.
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