TLR2 Regulates Mast Cell IL-6 and IL-13 Production During Listeria monocytogenes Infection

Listeria monocytogenes (L.m) is efficiently controlled by several cells of the innate immunity, including the Mast Cell (MC). MC is activated by L.m inducing its degranulation, cytokine production and microbicidal mechanisms. TLR2 is required for the optimal control of L.m infection by different cells of the immune system. However, little is known about the MC receptors involved in recognizing this bacterium and whether these interactions mediate MC activation. In this study, we analyzed whether TLR2 is involved in mediating different MC activation responses during L.m infection. We found that despite MC were infected with L.m, they were able to clear the bacterial load. In addition, MC degranulated and produced ROS, TNF-α, IL-1β, IL-6, IL-13 and MCP-1 in response to bacterial infection. Interestingly, L.m induced the activation of signaling proteins: ERK, p38 and NF-κB. When TLR2 was blocked, L.m endocytosis, bactericidal activity, ROS production and mast cell degranulation were not affected. Interestingly, only IL-6 and IL-13 production were affected when TLR2 was inhibited in response to L.m infection. Furthermore, p38 activation depended on TLR2, but not ERK or NF-κB activation. These results indicate that TLR2 mediates only some MC activation pathways during L.m infection, mainly those related to IL-6 and IL-13 production.

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Imidacloprid exposure suppresses cytokine production and neutrophil infiltration in TLR2-dependent activation of RBL-2H3 cells and skin inflammation of BALB/c mice

New Journal of Chemistry ◽

10.1039/d0nj01945c ◽

2020 ◽

Vol 44 (45) ◽

pp. 19489-19498

Author(s):

Linbo Shi ◽

Huaping Xu ◽

Fangfang Min ◽

Xin Li ◽

Xiaoyun Shi ◽

...

Keyword(s):

Mast Cell ◽

Cytokine Production ◽

Neutrophil Infiltration ◽

Skin Inflammation ◽

Mast Cell Degranulation ◽

Tnf Α

Imidacloprid suppressed TNF-α and IL-6 production and neutrophil infiltration, without altering mast cell degranulation.

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Once Phosphorylated, Tyrosines in Carboxyl Terminus of Protein-tyrosine Kinase Syk Interact with Signaling Proteins, Including TULA-2, a Negative Regulator of Mast Cell Degranulation

Journal of Biological Chemistry ◽

10.1074/jbc.m111.326850 ◽

2012 ◽

Vol 287 (11) ◽

pp. 8194-8204 ◽

Cited By ~ 26

Author(s):

Rodrigo Orlandini de Castro ◽

Juan Zhang ◽

Jacqueline R. Groves ◽

Emilia Alina Barbu ◽

Reuben P. Siraganian

Keyword(s):

Mast Cell ◽

Tyrosine Kinase ◽

Protein Tyrosine Kinase ◽

Mast Cell Degranulation ◽

Negative Regulator ◽

Carboxyl Terminus ◽

Signaling Proteins ◽

Protein Tyrosine

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CD1d-independent regulation of NKT cell migration and cytokine production upon Listeria monocytogenes infection

Cellular Immunology ◽

10.1016/j.cellimm.2005.01.009 ◽

2004 ◽

Vol 232 (1-2) ◽

pp. 38-48 ◽

Cited By ~ 10

Author(s):

Victor Arrunategui-Correa ◽

Laurel Lenz ◽

Hyun Sil Kim

Keyword(s):

Cell Migration ◽

Listeria Monocytogenes ◽

Cytokine Production ◽

Nkt Cell ◽

Listeria Monocytogenes Infection

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SGLT1 Deficiency Turns Listeria Infection into a Lethal Disease in Mice

Cellular Physiology and Biochemistry ◽

10.1159/000479197 ◽

2017 ◽

Vol 42 (4) ◽

pp. 1358-1365 ◽

Cited By ~ 8

Author(s):

Piyush Sharma ◽

Vishal Khairnar ◽

Ivana Vrhovac Madunić ◽

Yogesh Singh ◽

Aleksandra Pandyra ◽

...

Keyword(s):

Listeria Monocytogenes ◽

Glucose Uptake ◽

Bacterial Load ◽

Bacterial Clearance ◽

Wild Type ◽

Hepatic Expression ◽

Cell Functions ◽

Tnf Α ◽

Listeria Infection ◽

Deficient Mice

Background: Cellular glucose uptake may involve either non-concentrative glucose carriers of the GLUT family or Na+-coupled glucose-carrier SGLT1, which accumulates glucose against glucose gradients and may thus accomplish cellular glucose uptake even at dramatically decreased extracellular glucose concentrations. SGLT1 is not only expressed in epithelia but as well in tumour cells and immune cells. Immune cell functions strongly depend on their metabolism, therefore we hypothesized that deficiency of SGLT1 modulates the defence against bacterial infection. To test this hypothesis, we infected wild type mice and gene targeted mice lacking functional SGLT1 with Listeria monocytogenes. Methods: SGLT1 deficient mice and wild type littermates were infected with 1x104 CFU Listeria monocytogenes intravenously. Bacterial titers were determined by colony forming assay, SGLT1, TNF-α, IL-6 and IL-12a transcript levels were determined by qRT-PCR, as well as SGLT1 protein abundance and localization by immunohistochemistry. Results: Genetic knockout of SGLT1 (Slc5a1–/– mice) significantly compromised bacterial clearance following Listeria monocytogenes infection with significantly enhanced bacterial load in liver, spleen, kidney and lung, and significantly augmented hepatic expression of TNF-α and IL-12a. While all wild type mice survived, all SGLT1 deficient mice died from the infection. Conclusions: SGLT1 is required for bacterial clearance and host survival following murine Listeria infection.

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Faculty Opinions recommendation of The Bcl10-Malt1 complex segregates Fc epsilon RI-mediated nuclear factor kappa B activation and cytokine production from mast cell degranulation.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1021643.374596 ◽

2006 ◽

Author(s):

Ricardo Saban

Keyword(s):

Mast Cell ◽

Nuclear Factor Kappa B ◽

Cytokine Production ◽

Mast Cell Degranulation ◽

Nuclear Factor ◽

Nuclear Factor Kappa

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P-21 Activated Kinase 1 (Pak1) Is Critical for Normal Mast Cell Degranulation and Cytokine Production in Response to Antigen Stimulation of the High Affinity IgE Receptor.

Blood ◽

10.1182/blood.v104.11.647.647 ◽

2004 ◽

Vol 104 (11) ◽

pp. 647-647

Author(s):

Jayme D. Allen ◽

Clemens Hoffman ◽

Ethel Derr-Yellin ◽

Waylan Bessler ◽

Fen-Chun Yang ◽

...

Keyword(s):

Mast Cell ◽

Transcription Factors ◽

Cytokine Production ◽

De Novo ◽

Mast Cell Degranulation ◽

Ige Receptor ◽

High Affinity ◽

Cytokine Synthesis ◽

High Affinity Ige Receptor ◽

Stimulation Of

Abstract Mast cells participate in normal and pathogenic inflammatory processes, including innate host defense, allergy, and asthma. Stimulation of the mast cell high-affinity IgE receptor (FcεR) by receptor cross-linking activates multiple downstream signaling pathways resulting in degranulation and de novo synthesis of multiple cytokines. However, the molecular mechanisms underlying these processes are incompletely defined. It is known that Rac2 deficient murine bone marrow derived mast cells (BMMCs) have impaired degranulation, but the downstream effectors that modulate this function are unknown. We hypothesized that p-21 activated kinase 1 (Pak1), a downstream effector of Rac proteins, is important in degranulation and de novo cytokine synthesis. Mature BMMCs from wild-type (WT) and Pak1 KO mice were sensitized with anti-DNP IgE then stimulated with DNP-HSA to stimulate FcεR. Interestingly, Pak1 KO BMMCs showed significant impairment in degranulation, as demonstrated by a 3-fold reduction in the percent of B-hexosaminidase released upon IgE stimulation. IgE stimulation of mast cell results not only in degranulation, but also in the production of TNFα, which is critical in the early recruitment of neutrophils to sites of acute inflammation. TNFαsynthesis is influenced by a number of transcription factors, many which are regulated by Erk. Since Pak1 has been shown, in overexpression systems, to phosphorylate Raf and Mek to activate Erk, we examined Erk activation in WT and Pak1 KO BMMCs in response to IgE stimulation. Pak1 KO BMMCs have a 50% reduction in phospho-Erk as compared to controls. We then tested another MAPK member important in mast cell cytokine synthesis, p38, and found phospho-p38 to be decreased in Pak1 KO BMMCs as well. Further, IgE-stimulated Pak1 KO BMMCs produce only 20–30% as much TNFαas controls. To define the role of Pak1 in cytokine production as specific for TNFαversus a more global defect, we also studied IL-6 synthesis and are able to report a 50% reduction in IL-6 production by Pak1 KO BMMCs. Our results indicate that Pak1 is important in BMMC degranulation, cytokine production, and MAPK activation in response to FcεR stimulation. These studies identify Pak1 as a potential therapeutic target in pathologic inflammation. Mechanisms by which Pak1 may be influencing mast cell degranulation as well as further study of transcription factors important in mast cell cytokine production are under current investigation.

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Regulation of mast cell survival and function by tuberous sclerosis complex 1

Blood ◽

10.1182/blood-2011-05-353342 ◽

2012 ◽

Vol 119 (14) ◽

pp. 3306-3314 ◽

Cited By ~ 28

Author(s):

Jinwook Shin ◽

Hongjie Pan ◽

Xiao-Ping Zhong

Keyword(s):

Mast Cell ◽

Mast Cells ◽

Cell Survival ◽

Tuberous Sclerosis ◽

Tuberous Sclerosis Complex ◽

Cell Activation ◽

Cytokine Production ◽

Mast Cell Degranulation ◽

Mtor Signaling ◽

Mast Cell Activation

Abstract Mast cells play critical roles in allergic disorders and asthma. The importance of tuberous sclerosis complex 1/2-mammalian target of rapamycin (TSC1/2-mTOR) signaling in mast cells is unknown. Here, we report that TSC1 is a critical regulator for mTOR signaling in mast cells downstream of FcεRI and c-Kit, and differentially controls mast cell degranulation and cytokine production. TSC1-deficiency results in impaired mast cell degranulation, but enhanced cytokine production in vitro and in vivo after FcεRI engagement. Furthermore, TSC1 is critical for mast cell survival through multiple pathways of apoptosis including the down-regulation of p53, miR-34a, reactive oxygen species, and the up-regulation of Bcl-2. Together, these findings reveal that TSC1 is a critical regulator of mast cell activation and survival, suggesting the manipulation of the TSC1/2-mTOR pathway as a therapeutic strategy for mast cell-mediated diseases.

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