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Immediate Cytokine Responses to Endotoxin: Tumor Necrosis Factor-α and the lnterleukin-1 Family
Published in Helmut Brade, Steven M. Opal, Stefanie N. Vogel, David C. Morrison, Endotoxin in Health and Disease, 2020
Consistent with the induction of TNF in these models is the observation that IL-18 induces human immunodeficiency virus-1 (HIV-1) expression. At concentrations as low as 100 pM, mature IL-18 induces p24 synthesis in a chronically infected macrophage cell line called U1 (61). The increase in p24 is an indication of production of competent virus by these cells. Similar to the observation in PBMC, HIV-1 p24 production by IL-18 is inhibited by blocking the activity of endogenously produced TNF (61). Furthermore, the induction of p24 by IL-18 is reduced by inhibition of endogenous nitric oxide synthesis (62). Again, these observations are consistent with the ability of IL-18 to activate N F kB translocation. As discussed below, one chain of the IL-18 receptor complex is the IL-lRrp, which upon transient transfection into COS-1 cells results in NFκB translocation (57). In murine cloned T cells, IL-18 stimulation results in a macromolecular complex precipitated by an antibody to IRAK (66). In these same cells, IL-18 does not activate STAT 4, which characteristically occurs following IL-12 treatment (66). Since IRAK activates a kinase cascade leading to degradation of IκB and activation of NFκB, these findings are consistent with IL-18 induction of TNF from T cells and IL-8 from macrophages (55).
Sjögren Syndrome
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
The STAT4 (signal transducer and activator of transcription 4, particularly the third intron) gene encodes a transcription factor that is vital for type I interferon-initiated cellular responses. After induction by IL-12 in lymphocytes, STAT4 contributes to the transcription of interferon-γ, and plays a partial role (along with IRF5 and TNIP1) in the development of SLE and rheumatoid arthritis [5].
JAK-STAT pathway: Testicular development, spermatogenesis and fertility
Published in Rajender Singh, Molecular Signaling in Spermatogenesis and Male Infertility, 2019
In mammals, there are four JAK family members; out of these TYK2 (81), JAK1 (41) and JAK2 (80) were found in human spermatozoa. The phosphorylation of JAK proteins, in response to ligand-receptor interactions, induces the activation of STAT proteins. Initially, STAT1 and STAT4 were detected in human spermatozoa (81). Another study by Lachance and Leclerc also detected STAT3, STAT5 and STAT6 in human spermatozoa (76). The STAT proteins in addition to acting as transcription factors are known to interact with tubulin binding proteins, thus facilitating protein-protein interactions (82). However, the latter needs further exploration.
Association of STAT4 Gene Rs7574865, Rs10168266 Polymorphisms and Systemic Lupus Erythematosus Susceptibility: A Meta-analysis
Published in Immunological Investigations, 2021
Jia-Min Wang, Wang-Dong Xu, an-Fang Huang
Signal transducer and activator of transcription 4 (STAT4) gene is located on chromosome 6q33 in human and encodes STAT4 transcription factor. This molecule is mainly expressed in T cells, NK cells and belongs to the STAT protein family (Gupta et al. 2018; Hagberg et al. 2018). Interleukin-12 (IL-12) activates STAT4 via altering histone modifications. Phosphorylated STAT4 is transported to the nucleus which combines with DNA binding sites in target gene regulatory elements to promote Th1 cell differentiation and proliferation, and activate interferon (IFN)-γ. The cytokine IFN-γ exerts proinflammatory role in autoimmunity (Goropevšek et al. 2017; Ma et al. 2018). In addition, STAT4 contributes to the differentiation of Th17 cells (Mathur et al. 2007). Given the important role of Th1, Th17 cells and their associated cytokines in SLE pathogenesis, it is speculated that STAT4 may involve in SLE development by regulating Th1, Th17 cells and related cytokines.
Expression of genes and pathways associated with the B7-CD28 superfamily in response to irradiation of blood cells using 137Cs
Published in International Journal of Radiation Biology, 2021
Daner A. Silveira, Fernanda M. Ribeiro, Éder M. Simão, Viviane L. D. Mattos, Evamberto G. Góes
The pathway of the adaptive immune system showed a significant decrease in relative activity and diversity at 600 cGy. This pathway contains genes related to the adaptive immune response (Pancer and Cooper 2006). Thus, these results suggest that IR can induce an immunosuppressive effect. This suggests that the 600 cGy dose is sufficiently strong to significantly decrease the activity of the immune system. Moreover, the down-regulation of CD28, GATA3, STAT4, and TBX21 observed in our study can contribute to this immunosuppressive effect. CD28 can induce stimulatory signals for the T cell activation through interaction with CD80, CD86, and ICOSLG (Sharpe and Freeman 2002). GATA3, in turn, induces the activation of IL4, which can regulate the differentiation of Th2 cells (Ouyang et al. 1998, 2000; Zhu et al. 2003). STAT4 is also associated with the stimulation of cytokine expressions, such as IFNG in Th1 cells (Frucht et al. 2000; Pearce et al. 2003; Cruz-Guilloty et al. 2009). The down-regulation of TBX21 might indicate the inhibition of the T cell differentiation in Th1 and Th2 (Kanhere et al. 2012). Although we observed the significant decrease of the relative diversity of the adaptive immune system pathway for 150 cGy, this dose does not affect the relative activity, which is associated with the pathway activation.
Liuweibuqi capsules improve pulmonary function in stable chronic obstructive pulmonary disease with lung-qi deficiency syndrome by regulating STAT4/STAT6 and MMP-9/TIMP-1
Published in Pharmaceutical Biology, 2019
Dan-Dan Shen, Zhong-Hui Yang, Ji Huang, Fei Yang, Zi-Wei Lin, Ying-Fei Ou, Min-Hao Hu
Liuweibuqi (LWBQ) capsules are a type of Traditional Chinese Medicine (TCM), which comprise of Renshen, Yuzhu, Huangqi, Rougui, Yizhi, and Chenpi (Wang et al. 2017a). Previous research found that LWBQ capsules can reduce the inflammatory reaction, thereby improving the symptoms of COPD by modulating the expression of matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) (Wang et al. 2015). MMP’s are prominent mediators in the turnover of extracellular matrix (ECM), which is maintained by the balanced expression between the pro- and anti-proteolytic factors including MMP-9 and its specific inhibitor-TIMP-1 (Barr et al. 2010). The signal transducer and activator of transcription (STAT) proteins, which are composed of a family of cytoplasmic transcription factors, critically function by modulating a variety of biological processes (Page et al. 2013). Previous studies have demonstrated the vital roles of both STAT4 and STAT6 in immune responses against inflammation in patients with inflammatory bowel diseases and in Alternaria-induced asthma mice (Kim et al. 2012; Wu et al. 2016). In the present study, a total of 429 patients diagnosed as stable COPD with lung-qi deficiency syndrome were selected and treated with different doses of LWBQ capsules. Then the effect of LWBQ capsules on stable COPD with lung-qi deficiency syndrome and its underlying mechanism with STAT4/STAT6 and MMP-9/TIMP-1 were illustrated.