Faculty Opinions recommendation of The role of TTP phosphorylation in the regulation of inflammatory cytokine production by MK2/3.

2020 ◽  
Author(s):  
John Silke
Keyword(s):  
Inflammatory Cytokine ◽  
Cytokine Production ◽  
Inflammatory Cytokine Production

scholarly journals The Role of TTP Phosphorylation in the Regulation of Inflammatory Cytokine Production by MK2/3

2019 ◽  
Vol 203 (8) ◽  
pp. 2291-2300 ◽  
Author(s):  
Natalia Ronkina ◽  
Nelli Shushakova ◽  
Christopher Tiedje ◽  
Tatiana Yakovleva ◽  
Maxim A. X. Tollenaere ◽  
...  
Keyword(s):  
Inflammatory Cytokine ◽  
Cytokine Production ◽  
Inflammatory Cytokine Production

scholarly journals Dysregulated Macrophage Pro-Inflammatory Cytokine Production and Chronic Colitis in Mice Lacking Both Gab2 and Gab3

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 457-457
Author(s):  
Tamisha Y. Vaughan-Whitley ◽  
Hikaru Nishio ◽  
Barry Imhoff ◽  
Zhengqi Wang ◽  
Silvia T. Bunting ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Protein Expression ◽  
Knockout Mice ◽  
Inflammatory Cytokine ◽  
Cytokine Production ◽  
Wild Type ◽  
Inflammatory Cytokine Production ◽  
Tnf Α ◽  
Single Knockout

Abstract Macrophages are responsible for protecting the body against foreign invaders. We have been studying the role of Grb2-associated binding proteins (Gabs) in macrophage biology. In mice, Gabs are adaptor proteins that include three family members (Gab1, Gab2, and Gab3) that play critical regulatory roles in modulating cytokine receptor signaling. Gab2 knockout mice have no developmental defects but have impaired allergic responses, osteoclast defects, altered mast cell development, and altered hematopoiesis. Gab3 knockout mice have no defined phenotypes alone and although highly expressed in macrophages, a functional role was not found despite considerable focus on this cell type. Therefore, we set out to determine the combined role of Gab2 and Gab3 to determine whether they performed redundant functions not observable in single knockout mice. To analyze regulation of macrophage cytokine production, a Gab2/3 deficient mouse model was generated on the C57BL/6 background. Bone Marrow Derived Macrophages (BMDM) were expanded from the bone marrow (BM) of wild-type (WT), Gab2 and Gab3 single knockout and Gab2/3 knockout mice and found to similarly co-express CD11b and F4/80. However, Gab2/3 knockout BM produced only 30% of wild-type BMDM numbers. Despite reductions in BMDM absolute numbers, isolated BMDM demonstrated significant induction of pro-inflammatory cytokines TNF-α and IL-12 and anti-inflammatory cytokine IL-10 mRNA at baseline. Interestingly, after LPS stimulation (100ng/ml) we detected much greater induction of TNF-α and IL-12 mRNA and protein expression. Interestingly, despite increased IL-10 mRNA induction in Gab2/3 knockout BMDM, no IL-10 protein expression could be detected by Luminex assay. No changes were observed in production of interferon or STAT1 activation in these BMDM. Studies have shown that rapamycin treatment of macrophages suppresses mTORC1 and subsequently reduces IL-10 production and promotes pro-inflammatory cytokine production. Gab2 is known for its role in regulating the PI3K pathway through interactions with the p85 regulatory subunit of PI3K. Therefore, we also examined whether mTOR activation was effected by Gab2/3 deficiency causing altered cytokine expression. Deletion of Gab2/3 in BMDMs treated with LPS showed an inhibition of 4EBP1 phosphorylation and increased AKT phosphorylation. These results suggest that Gabs may play a critical role in modulating mTOR activation and potentially causing defects in protein translation that reflect in reduced IL-10 cytokine levels in Gab2/3 knockout cells. IL-10 has a critical immunoregulatory role that is dysregulated in patients with inflammatory bowel disease. IL-10 deficient mice develop colitis due to loss of mucosal immune tolerance. Strikingly, as early as two months of age in vivo 12/32 (37.5%) Gab2/3 knockout mice developed rectal prolapse and suffered from diarrhea within a six month period. Histological analysis of isolated colons using a scoring system confirmed spontaneous development of colitis in Gab2/3 knockout mice compared to no phenotypes observed in WT and single knockout controls. To determine whether the BM was directly involved in the disease, BM chimeras were generated using irradiated WT mice as recipients and Gab2/3 knockout mice as donors. Susceptible recipients receiving Gab2/3 knockout BM showed a more invasive colitis phenotype than the spontaneous disease and resulted in forced euthanization due to body weight decreases greater than 25%. Multiple ulcerations were present in most of the colon proximal region, with extensive epithelial damage, transmural inflammation, and in some mice adenocarcinoma. Notably, we did not observe adenocarcinoma in untransplanted Gab2/3 knockout mice, suggesting that epithelial deletion of Gab2/3 may suppress cancer whereas in the bone marrow chimera model, the epithelial cells are WT and can be transformed. Similar phenotypes were also observed in secondary transplant recipients. Lastly, treatment of Gab2/3 knockout mice with dextran-sodium-sulfate (DSS) induced rapid severe colitis that resulted in death of 80% and 40% of Gab2/3 knockout and WT mice respectively. Overall, these observations demonstrate a major redundant role for Gab2 and Gab3 in macrophage immune surveillance required for the prevention of colitis in mice. Disclosures No relevant conflicts of interest to declare.

scholarly journals Neutrophil-Derived Semaphorin 4D Induces Inflammatory Cytokine Production of Endothelial Cells via Different Plexin Receptors in Kawasaki Disease

2020 ◽  
Vol 2020 ◽  
pp. 1-11
Author(s):  
Junhua Huang ◽  
Shouzhen Wu ◽  
Sancheng Cao ◽  
Xieying Zhu ◽  
Shuwan Zhang
Keyword(s):  
Endothelial Cells ◽  
Kawasaki Disease ◽  
Inflammatory Cytokine ◽  
Cytokine Production ◽  
Serum Concentrations ◽  
Inflammatory Cytokine Production ◽  
Semaphorin 4D ◽  
Proinflammatory Effect ◽  
Coronary Endothelial Cells

Inflammation of endothelial cells (ECs) plays an important role in the pathogenesis of coronary artery lesions (CALs) in Kawasaki disease (KD). Semaphorin 4D (Sema4D) is the first semaphorin shown to have immunoregulatory functions by interacting with its receptors—plexin Bs. Recently, Sema4D has been reported to exert a proinflammatory effect on the endothelium and to be involved in cardiovascular disease. However, the role of Sema4D in KD remains unknown. This study was aimed at revealing the change of soluble Sema4D (sSema4D) in the serum of patients with KD and the effect of the sSema4D-plexin axis on the production of proinflammatory cytokines from human coronary endothelial cells (HCAECs) stimulated with sera from KD patients. Our results showed that serum sSema4D levels were specifically elevated in KD patients, especially in those with CALs, and correlated positively with disease severity and serum concentrations of interleukin- (IL-) 1β, IL-6, and IL-8. The disintegrin and metalloproteinase domain 17- (AMAM17-) mediated Sema4D shedding from neutrophils contributed to the elevation of sSema4D in the serum of KD patients. Furthermore, we found that Sema4D induced IL-1β production of HCAECs via plexin B2, whereas it promoted IL-6 and IL-8 production via plexin B1. Moreover, the expression of both plexin B1 and plexin B2 was upregulated in HCAECs treated with KD sera, and silencing of the two plexin receptors suppressed the overexpression of IL-1β, IL-6, and IL-8 in KD serum-treated HCAECs. Thus, our findings indicated that sSema4D released from neutrophils participates in the pathogenesis of KD-CALs by promoting inflammatory cytokine production of ECs via both plexin B1 and plexin B2, and Sema4D may be a novel predictor for KD-CALs and a candidate therapeutic target for anti-inflammatory strategies of KD.

The Strong and the Weak - the Dual Role of JAK1 in Inflammatory Cytokine Production,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3218-3218
Author(s):  
Thomas Luft ◽  
Andreas Wagner ◽  
Michael Conzelmann ◽  
Sascha Dietrich ◽  
Oliver Krämer ◽  
...  
Keyword(s):  
Inflammatory Cytokine ◽  
Cytokine Production ◽  
Conflicts Of Interest ◽  
Human Monocyte ◽  
Dual Role ◽  
Inflammatory Cytokine Production ◽  
E Coli ◽  
Sirna Silencing ◽  
Clinical Concept

Abstract Abstract 3218 Inhibition of JAK1 is an emerging clinical concept that has promise for a variety of autoimmune diseases, myeloproliferative diseases and post-transplant immunosuppression, but similarly raises concerns regarding immunosuppressive side effects. At the example of IL-12p70 production in human monocyte-derived dendritic cells we demonstrate that JAK1 has a dual role in differentially regulating effects of weak and strong activation stimuli. We have demonstrated recently that weak NF-kB-activating stimuli (e.g. CD40L or LPS) require complementary JAK1-targeting cytokines such as IFN-g to induce IL-12p70. This pathway involves RELA, CREL, JAK1 and/or JAK2, STAT1, IRF1 and IRF8 and is inhibited by RELB and TYK2 (Conzelmann et al. Biochem Pharm. 2010, 80(12):2074–86). Here we provide evidence for an alternative IL-12 stimulating pathway depending on strong NF-kB activating stimuli (e.g. intact E. coli or LPS plus IL-1b). siRNA silencing demonstrated that this pathway is specifically inhibited by JAK1 and the transcription factor STAT3, but is not influenced by any of the other JAK/STAT family members. Both IL-12p35 and p40 mRNA expression is directly inhibited by STAT3. Furthermore, ChIP-assays revealed that STAT3 binds directly to a combined STAT/NF-kB site at the IL-12p35 promoter without altering access of RELA and CREL. Extending the cytokine panel we found that E.coli-induced IL-6 and TNF-a production is similarly inhibited by the JAK1/STAT3 pathway whereas IL-10 expression is not affected. The observed dual effects of JAK1 are clearly confirmed by the JAK1/2 inhibitor INCB018424 (Ruxolitinib) which enhances E.coli-induced cytokines whilst strongly inhibiting cytokine production stimulated by CD40L/IFN-g. In summary, our study suggests that blockade of JAK1 specifically inhibits pro-inflammatory effects of weak, IFN-g dependent, NF-kB activating stimuli while enhancing inflammatory cytokine expression induced by strong activation stimuli. Inhibition of JAK1/2 by INCB018424 (Ruxolitinib) would therefore represent a novel immunosuppressive approach that may spare the immune defence against invading pathogens. Disclosures: No relevant conflicts of interest to declare.

scholarly journals C4b binding protein negatively regulates TLR1/2 response

2016 ◽  
Vol 23 (1) ◽  
pp. 11-19 ◽  
Author(s):  
Naoko Morita ◽  
Ikuko Yamai ◽  
Koichiro Takahashi ◽  
Yutaka Kusumoto ◽  
Takuma Shibata ◽  
...  
Keyword(s):  
Inflammatory Cytokine ◽  
Cytokine Production ◽  
Binding Protein ◽  
Negative Regulation ◽  
Negative Regulator ◽  
Wild Type ◽  
Inflammatory Cytokine Production ◽  
Inflammatory Signals ◽  
Deficient Mice

TLR2 associates with TLR1 and recognizes microbial lipoproteins. Pam3CSK4, a triacylated lipoprotein, is anchored to the extracellular domain of TLR1 and TLR2 and induces pro-inflammatory signals. Here we show that C4b binding protein (C4BP), which is a complement pathway inhibitor, is a TLR2-associated molecule. Immunoprecipitation assay using anti-TLR2 mAb shows that C4BP binds to TLR2. In C4BP-deficient mice, Pam3CSK4-induced IL-6 levels were increased compared with wild type mice. In C4BP-expressing cells, Pam3CSK4-induced IL-8 production was reduced depending on the C4BP expression levels. These results reveal the important role of C4BP in negative regulation of TLR1/2-dependent pro-inflammatory cytokine production. Furthermore, using a fluorescent conjugated Pam3CSK4, we show that C4BP blocks the binding of Pam3CSK4 to TLR1/2. Finally, we show that exogenous C4BP also inhibits Pam3CSK4-induced signaling leading to IL-8 production. Our results indicate C4BP binding to TLR2 and consequent neutralization of its activity otherwise inducing pro-inflammatory cytokine production. C4BP is a negative regulator of TLR1/2 activity.

scholarly journals The Role of JAK-3 in Regulating TLR-Mediated Inflammatory Cytokine Production in Innate Immune Cells

2013 ◽  
Vol 191 (3) ◽  
pp. 1164-1174 ◽  
Author(s):  
Huizhi Wang ◽  
Jonathan Brown ◽  
Shegan Gao ◽  
Shuang Liang ◽  
Ravi Jotwani ◽  
...  
Keyword(s):  
Immune Cells ◽  
Inflammatory Cytokine ◽  
Cytokine Production ◽  
Innate Immune ◽  
Innate Immune Cells ◽  
Inflammatory Cytokine Production

Role of Brd4 in the production of inflammatory cytokines in mouse macrophages treated with titanium particles

2019 ◽  
Vol 97 (11) ◽  
pp. 1028-1034 ◽  
Author(s):  
Yuanzhong Ren ◽  
Yongtao Zhang ◽  
Ze Wang ◽  
Changyao Wang ◽  
Haining Zhang ◽  
...  
Keyword(s):  
Inflammatory Cytokines ◽  
Inflammatory Cytokine ◽  
Cytokine Production ◽  
Wear Particle ◽  
Raw264.7 Cells ◽  
Inflammatory Cytokine Production ◽  
Tnf Α ◽  
Mouse Macrophages ◽  
Ti Particles

Brd4 protein is an important epigenetic regulator involved in the process of inflammatory cytokine production in many diseases. However, whether and how Brd4 participates in the process of wear-particle-induced inflammation remain unclear. This study aimed to investigate the potential role of Brd4 in titanium (Ti) particle-induced inflammatory cytokine production in mouse macrophage RAW264.7 cells. Our experiment detected Brd4 expressed in both normal synovium and periprosthetic osteolysis interface membrane, but the expression increased in the interface membrane as compared with that in normal synovium. Treatment with Ti particles significantly increased TNF-α, IL-6, and IL-1β production in RAW264.7 cells, which was inhibited by JQ1 or Brd4-siRNA. Ti particles enhanced the expression of Brd4, which was abrogated by JQ1. Ti particles enhanced NF-κB p65 and IKK phosphorylation and attenuated IκBα protein expression, which were abrogated by JQ1. Co-immunoprecipitation analysis indicated that Ti particles promoted the binding of Brd4 to acetylated NF-κB p65 (lysine-310), which was also abrogated in JQ1-treated RAW264.7 cells. In conclusion, Brd4 expression increases in interface membrane and Brd4 participates in the production of pro-inflammatory cytokines induced by Ti particles via promoting the activation of NF-κB signaling and binding to acetylated NF-κB p65 (lysine-310) in mouse macrophages.

scholarly journals Bone marrow CX3CR1+ mononuclear cells relay a systemic microbiota signal to control hematopoietic progenitors in mice

Blood ◽  
2019 ◽  
Vol 134 (16) ◽  
pp. 1312-1322 ◽  
Author(s):  
Seungwon Lee ◽  
Hyekang Kim ◽  
Gihoon You ◽  
Young-Min Kim ◽  
Seunghun Lee ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Steady State ◽  
Inflammatory Cytokine ◽  
Mononuclear Cells ◽  
Cytokine Production ◽  
Myeloid Cell ◽  
Cell Maturation ◽  
Hematopoietic Progenitors ◽  
Inflammatory Cytokine Production

Abstract Lee and colleagues investigated the role of the intestinal microbiota in steady-state hematopoieisis, demonstrating that microbiota-derived DNA circulates to the bone marrow, where uptake by mononuclear cells leads to inflammatory cytokine production favoring myeloid-cell maturation of hematopoietic progenitors.

scholarly journals NFAM1 Promotes Pro-Inflammatory Cytokine Production in Mouse and Human Monocytes

2022 ◽  
Vol 12 ◽  
Author(s):  
Kathryn W. Juchem ◽  
Anshu P. Gounder ◽  
Jian Ping Gao ◽  
Elise Seccareccia ◽  
Narayana Yeddula ◽  
...  
Keyword(s):  
B Cell ◽  
Inflammatory Cytokine ◽  
Cytokine Production ◽  
Immune Cell ◽  
Cellular Level ◽  
Human Monocytes ◽  
Inflammatory Cytokine Production ◽  
Tnf Α

NFAT activating protein with ITAM motif 1 (NFAM1) is an ITAM bearing-transmembrane receptor that has been reported to play a role in B cell signaling and development. We performed expression analysis of NFAM1 using publicly available gene expression data sets and found that NFAM1 expression is significantly induced in intestinal biopsies from Crohn’s disease (CD) and ulcerative colitis (UC) patients. At the cellular level, we further observed high expression of NFAM1 in monocytes and neutrophils, and low expression in B and T cells. To explore the role of NFAM1 in multiple immune cells and its potential role in IBD, we generated NFAM1-/- mice. In contrast with previous reports using NFAM1-transgenic mice, NFAM1-/- mice have no obvious defects in immune cell development, or B cell responses. Interestingly, NFAM1-/- monocytes produce reduced levels of TNF-α in response to activation by multiple IBD-relevant stimuli, including CD40L, TLR ligands and MDP. Additional cytokines and chemokines such as IL-6, IL-12, CCL3 and CCL4 are also reduced in CD40L stimulated NFAM1-/- monocytes. Collectively, these findings indicate that NFAM1 promotes monocyte activation, thereby amplifying the response to diverse stimuli. Similarly, we observed that deletion of NFAM1 in human monocytes reduces expression of CD40L-induced CCL4. Lastly, to assess the role of NFAM1 in IBD, we compared development of anti-CD40 induced colitis in NFAM1+/+ and NFAM1-/- mice. We found that although NFAM1 deletion had no impact on development of gut pathology, we did observe a decrease in serum TNF-α, confirming that NFAM1 promotes pro-inflammatory cytokine production in vivo. Taken together, we conclude that NFAM1 functions to amplify cytokine production and should be further evaluated as a therapeutic target for treatment of autoimmune disease.

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