The role of Janus kinase (JAK)-3 in TLR-mediated innate immune responses is poorly understood, although the suppressive function of JAK3 inhibition in adaptive immune response has been well studied. In this study, we found that JAK3 inhibition enhanced TLR-mediated immune responses by differentially regulating pro- and anti- inflammatory cytokine production in innate immune cells. Specifically, JAK3 inhibition by pharmacological inhibitors or specific siRNA, or JAK3 gene knockout resulted in an increase in TLR-mediated production of pro-inflammatory cytokines, while concurrently decreasing the production of IL-10. Inhibition of JAK3 suppressed phosphorylation of PI3 kinase downstream effectors including Akt, mTORC1, GSK3β and CREB. Constitutive activation of Akt or inhibition of GSK3β abrogated the capability of JAK3 inhibition to enhance pro-inflammatory cytokines and suppress IL-10 production. In contrast, inhibition of PI3K enhanced this regulatory ability of JAK3 in LPS stimulated monocytes. At the transcriptional level, JAK3 knockout lead to the increased phosphorylation of STATs that could be attenuated by neutralization of de novo inflammatory cytokines. JAK3 inhibition exhibited a GSK3 activity-dependent ability to enhance phosphorylation levels and DNA binding of NF-κB p65. Moreover, JAK3 inhibition correlated with an increased CD4+ T cell response. Additionally, higher neutrophil infiltration, IL-17 expression, and intestinal epithelium erosion were observed in JAK3 knockout mice. These findings demonstrate the negative regulatory function of JAK3, and elucidate the signaling pathway by which JAK3 differentially regulates TLR-mediated inflammatory cytokine production in innate immune cells.
Serum-and glucocorticoid-regulated kinase (SGK)1 is associated with several important pathologic conditions and plays a modulatory role in adaptive immune responses. However, the involvement and functional role of SGK1 in innate immune responses remain entirely unknown. In this study, we establish that SGK1 is a novel and potent negative regulator of TLR-induced inflammation. Pharmacologic inhibition of SGK1 or suppression by small interfering RNA enhances proinflammatory cytokine (TNF, IL-12, and IL-6) production in TLR-engaged monocytes, a result confirmed in Cre-loxPmediated SGK1-deficient cells. SGK1 inhibition or gene deficiency results in increased phosphorylation of IKK, IkBa, and NF-kB p65 in LPS-stimulated cells. Enhanced NF-kB p65 DNA binding also occurs upon SGK1 inhibition. The subsequent enhancement of proinflammatory cytokines is dependent on the phosphorylation of TGF-b-activated kinase 1 (TAK1), as confirmed by TAK1 gene silencing. In vivo relevance was established in a murine endotoxin model, in which we found that SGK1 inhibition aggravates the severity of multiple organ damage and enhances the inflammatory response by heightening both proinflammatory cytokine levels and neutrophil infiltration. These findings have identified an anti-inflammatory function of SGK1, elucidated the underlying intracellular mechanisms, and establish, for the first time, that SGK1 holds potential as a novel target for intervention in the control of inflammatory diseases.-
ObjectiveTo examine the relationship between cytokine levels of transforming growth factor-beta-1 (TGF-β1), interleukin-1 beta (IL-1β), and angiotensin-converting enzyme (ACE) in the plasma of esophageal carcinoma patients and radiation-induced pneumonitis (RP).Materials and methodsSixty-three patients with esophageal carcinoma were treated with three-dimensional conformal radiotherapy (RT) using the Elekta Precise treatment planning system with a prescribed dose of 50–70 Gy. Dose–volume histograms were collected from three-dimensional conformal RT to determine the volume percentage of the lung received V5, V10, V20, and the normal tissue complication probability. RP was diagnosed based on computed tomography imaging, respiratory symptoms, and signs. The severity of radiation-induced lung toxicity was determined using the Lent–Soma scale defined by the Radiation Therapy Oncology Group. Plasma samples obtained before RT, during RT (at 40 Gy), and at 1 day, 1 month, and 3 months after RT were assayed for TGF-β1, IL-1β, and ACE levels by enzyme-linked immunosorbent assay.ResultsFrom the 63 patients, 17 (27%) developed RP, and 13 (21%) had RP of grade I and four (6%) had grade II or higher. We found plasma TGF-β1 levels were elevated in the patients that had RP when compared with the other 46 patients who did not have RP. The plasma IL-1β levels were not changed. The ACE levels were significantly lower in the 17 patients with RP compared to the 46 patients without RP throughout the RT. As expected, RP is associated with a higher dose of irradiation (>60 Gy); no other factors, including dose–volume histogram, age, sex, smoking status, location of tumor, and methods of treatment, are associated with RP.ConclusionElevated plasma TGF-β1 levels can be used as a marker for RP.
2 (95%CI, 1.2-1.3). The prevalence in rural areas was higher than in urban areas (p<0.01), resulting in an overall rural:urban OR of 2.6 (95%CI, 2.4-2.9). The rural:urban ORs and the 95% CI increased continuously from 2.6, 2.3-3.0 to 2.7, 2.2-3.3, respectively, for 4 consecutive periods during the 22-yr study period. Moreover, the median age of onset among females was higher than that among males (p<0.01). For both sexes and in both areas, the prevalence rates declined and the median age of onset rose for 4 consecutive periods in the 22-yrs time frame (p<0.01). Conculsions: These data reveal the epidemiological profile of ESCC in the area of North China, and suggest that urban areas and rural people account for a growing proportion of the ESCC patients although the prevalence of ESCC significantly declined and the median age-of-onset postponed over the 22-yrs period. Moreover, the prevalence status of ESCC in rural areas also underlines the need for public health initiatives aimed at reducing risk factors of this fatal disease.
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