Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Proinflammatory cytokines of the IL-1 family play an important role for the anti-mycobacterial host defense mechanisms. In the present study we have deciphered the pathways leading from recognition of Mycobacterium tuberculosis to the production and release of IL-1beta, the most important member of the IL-1 family. By stimulating cells defective in various pattern recognition receptors, we could demonstrate that IL-1beta production is induced by M. tuberculosis through pathways involving TLR2/TLR6 and NOD2 receptors. In contrast, TLR4, TLR9 and TLR1 receptors are not involved in IL-1beta induction. Recognition of M. tuberculosis by TLR and NOD2 leads to transcription of proIL-1beta through mechanisms involving ERK, p38 and Rip2, but not JNK. Interestingly, although caspase-1 is necessary for the processing of proIL-1beta, activation of caspase-1 is not dependent on the stimulation of cells by M. tuberculosis. Monocytes expressed constitutively active caspase-1. The secretion of IL-1beta is dependent on the activation of P2X7-induced pathways by endogenously released ATP. In conclusion, we have dissected the molecular mechanisms responsible for IL-1beta production by M. tuberculosis, and that may contribute to a deeper knowledge of the mechanisms of cell activation by M. tuberculosis.
 ...
PMID:Transcriptional and inflammasome-mediated pathways for the induction of IL-1beta production by Mycobacterium tuberculosis. 1954 85

TLRs are known to be important in innate host defense against a variety of microbial infections. In particular, TLR9 has been associated with immune defense against different foreign organisms by recognition of unmethylated DNA sequences. In this report, we provide evidence that leukotriene B(4) (LTB(4)) has the capacity to modulate TLR9 expression on human neutrophils. The effect of LTB(4) was found to be specific, because related leukotrienes such as LTC(4) and LTD(4) or neutrophil agonists IL-8 and C5a failed to modulate TLR9 expression in neutrophils. Using fluorochrome-tagged CpG DNA, we observed that LTB(4) treatment also increased TLR9 ligand binding in neutrophils. Moreover, LTB(4) stimulation potentiates CpG-mediated signaling via an endosome-independent mechanism in human neutrophils, leading to enhanced secretion of proinflammatory cytokines. The increase in cytokine secretion by LTB(4) following CpG stimulation of neutrophils was associated with the activation of TGF-beta-activated kinase (TAK-1) as well as p38 and c-Jun (JNK) kinases. In contrast, in PBMC LTB(4) leads to an increase in cytokine secretion following CpG stimulation but via a MyD88- and endosome-dependent mechanism. As observed in neutrophils, PBMC stimulation with LTB(4) in the presence of CpG also results in enhanced TAK-1, p38, and JNK phosphorylation/activation. These data provide new evidence underlying the immunomodulatory properties of LTB(4) leading to antimicrobial defense.
 ...
PMID:Leukotriene B4 potentiates CpG signaling for enhanced cytokine secretion by human leukocytes. 1962 Feb 96

Interactions between innate and adaptive immune receptors are critical for an optimal immune response, but the role played by Ag receptors in modulating innate receptor functions is less clear. TLRs are a family of pattern recognition receptors that play crucial roles in detecting microbial pathogens and subsequent development of immune responses. However, chronic stimulation through TLRs renders immune cells hyporesponsive to subsequent stimulation with TLR ligands, a phenomenon known as TLR tolerance, well characterized in myeloid cells. However, it has not been studied in detail in B lymphocytes. In addition to the BCR, B cells express almost all known TLRs and respond robustly to many TLR ligands. Thus, B cells may receive signals through both TLRs and BCR during an infection and may respond differently to TLR stimulation than myeloid cells. We tested this possibility by stimulating repeatedly through either TLR alone or both TLR and BCR. Prestimulation through TLR7 resulted in reduced B cell proliferation, cytokine production, and IgM secretion upon subsequent TLR7 restimulation. The hyporesponsiveness to TLR7 restimulation was associated with reduced NF-kappaB and MAPK activation and defective c-Jun phosphorylation. However, simultaneous BCR signaling prevented or reversed TLR7 tolerance in both mouse and human B cells. Importantly, BCR signaling also rescued B cells from TLR7-mediated TLR9 tolerance. Additionally, the reversal of TLR7-mediated JNK activation was dependent on PI3K activation. Together these results present a novel mechanism to prevent and reverse TLR tolerance in B cells.
 ...
PMID:Antigen receptor signals rescue B cells from TLR tolerance. 1964 81

Stimulation of Toll-like receptors (TLRs) on macrophages and dendritic cells (DCs) by pathogen-derived products induces the production of cytokines, which play an important role in immune responses. Here, we investigated the role of the TPL-2 signaling pathway in TLR induction of interferon-beta (IFN-beta) and interleukin-10 (IL-10) in these cell types. It has previously been suggested that IFN-beta and IL-10 are coordinately regulated after TLR stimulation. However, in the absence of TPL-2 signaling, lipopolysaccharide (TLR4) and CpG (TLR9) stimulation resulted in increased production of IFN-beta while decreasing IL-10 production by both macrophages and myeloid DCs. In contrast, CpG induction of both IFN-alpha and IFN-beta by plasmacytoid DCs was decreased in the absence of TPL-2, although extracellular signal-regulated kinase (ERK) activation was blocked. Extracellular signal-related kinase-dependent negative regulation of IFN-beta in macrophages was IL-10-independent, required protein synthesis, and was recapitulated in TPL-2-deficient myeloid DCs by retroviral transduction of the ERK-dependent transcription factor c-fos.
 ...
PMID:TPL-2 negatively regulates interferon-beta production in macrophages and myeloid dendritic cells. 1966 62

Unmethylated CpG oligodeoxynucleotides (CpG-ODNs) interact with Toll-like receptor (TLR) 9 to activate macrophage/microglia in central nervous system (CNS). Here, we investigated the potential involvement of the chemokine CCL9 and its receptor CCR1 in the effects of CpG-ODNs on macrophage/microglial cells. CpG-ODNs enhanced the expression of TLR9 mRNA of RAW264.7 macrophage and BV2 microglia cells time dependently. The expression of CCL9 of macrophages/microglia showed different responsiveness upon stimulation with a variety of CpG-ODN sequences. The CpG-ODNs-mediated induction of CCL9 was TLR9/MyD88 dependent and associated with activation of stress kinases, particularly ERK, p38 MAPK and PI3K. The expression of CCR1 was also significantly increased by CpG-ODNs that increased CCL9 expression. These results reveal the potential involvement of CCL9 and CCR1 in regulation of macrophage and microglial cells by CpG-ODNs and may help improving our understanding about the role of the chemokine/chemokine receptor pairs in macrophage/microglia under physiologic and pathologic conditions.
 ...
PMID:CpG-ODNs induces up-regulated expression of chemokine CCL9 in mouse macrophages and microglia. 1988 4

The TLR family of pattern recognition receptors is largely responsible for meditating the activation of macrophages by pathogens. Because macrophages may encounter multiple TLR ligands during an infection, signaling crosstalk between TLR pathways is likely to be important for the tailoring of inflammatory reactions to pathogens. Here, we show that rather than inducing tolerance, LPS pretreatment primed the inflammatory response (e.g., TNF production) of mouse bone marrow-derived macrophages (BMM) to the TLR9 ligand, CpG DNA. The priming effects of LPS, which correlated with enhanced Erk1/2, JNK, and p38 MAPK activation, appeared to be mediated via both c-Fms-dependent and -independent mechanisms. LPS pretreatment and inhibition of the M-CSF receptor, c-Fms, with GW2580 had comparable effects on CpG DNA-induced Erk1/2 and p38 MAPK activation. However, c-Fms inhibition did not enhance CpG DNA-induced JNK activation; also, the levels of TNF produced were significantly lower than those from LPS-primed BMM. Thus, the priming effects of LPS on TLR9 responses appear to be largely mediated via the c-Fms-independent potentiation of JNK activity. Indeed, inhibition of JNK abrogated the enhanced production of TNF by LPS-pretreated BMM. The c-Fms-dependent priming effects of LPS are unlikely to be a consequence of the inhibitory constraints of M-CSF signaling on TLR9 expression being relieved by LPS; instead, LPS may exert its priming effects via signaling molecules downstream of TLR9. In summary, our findings highlight the importance of signaling crosstalk between TLRs, as well as between TLRs and c-Fms, in regulating the inflammatory reaction to pathogens.
 ...
PMID:Signaling crosstalk during sequential TLR4 and TLR9 activation amplifies the inflammatory response of mouse macrophages. 1992 61

In mammals, CpG mediated immune activation is initiated through toll-like receptor (TLR) 9 and Hsp90 via activation of MAPK/ERK and PI3K/AKT pathways. However, in the absence of TLR9 ortholog in chicken genome, the role of Hsp90 and kinase (MAPK/ERK and PI3K/AKT) pathways in initiating CpG ODN(2007) induced immune activation in chicken is not clear. Using electrophoretic mobility shift assay (EMSA) and selective inhibitors of signal transduction pathways, we determined the role of these pathways in the production of Th1 cytokines/chemokines and nitric oxide (NO) in CpG ODN(2007) treated avian macrophage cells. Hsp90alpha but not Hsp90beta is bound to CpG ODN(2007). Inhibition of Hsp90 with geldanamycin resulted in the inactivation of MAPK/ERK and PI3K/AKT pathways leading to significantly reduced levels of IFN-gamma, IL-6 and NO mRNAs in CpG ODN(2007) stimulated cells. Moreover, inhibition of ERK1/2 and PI3/AKT kinase pathways with PD985009 and LY294002, respectively, suppresses the phosphorylation of ERK2 and AKT leading to the production of decreased amounts of IFN-gamma, IL-6 and NO mRNAs in CpG ODN(2007) stimulated cells. Our results demonstrate that binding of CpG ODN(2007) to Hsp90 induces activation of ERK2 and AKT phosphorylation leading to the production of high levels of IFN-gamma, IL-6, MIP-3alpha and nitric oxide (NO). In contrast to mammals, our results suggest that Hsp90alpha but not Hsp90beta binds with the CpG ODN(2007) and may play a major role in CpG ODN(2007) induced immunoactivation in avian macrophage cells. To our knowledge, this is the first report evaluating the involvement of Hsp90 and kinase (MAPK/ERK and PI3K/AKT) pathways in CpG mediated immunostimulation in avian macrophage cells.
 ...
PMID:Role of Hsp90 in CpG ODN mediated immunostimulation in avian macrophages. 2009 33

Type I IFN signaling has recently been shown to be detrimental to the host during infection with Chlamydia muridarum in both mouse lung and female genital tract. However, the pattern recognition receptor and the signaling pathways involved in chlamydial-induced IFN-beta are unclear. Previous studies have demonstrated no role for TLR4 and a partial role for MyD88 in chlamydial-induced IFN-beta. In this study, we demonstrate that mouse macrophages lacking TLR3, TRIF, TLR7, or TLR9 individually or both TLR4 and MyD88, still induce IFN-beta equivalent to wild type controls, leading to the hypothesis that TLR-independent cytosolic pathogen receptor pathways are crucial for this response. Silencing nucleotide-binding oligomerization domain 1 in HeLa cells partially decreased chlamydial-induced IFN-beta. Independently, small interfering RNA-mediated knockdown of the stimulator of IFN gene (STING) protein in HeLa cells and mouse oviduct epithelial cells significantly decreased IFN-beta mRNA expression, suggesting a critical role for STING in chlamydial-induced IFN-beta induction. Conversely, silencing of mitochondria-associated antiviral signaling proteins and the Rig-I-like receptors, RIG-I, and melanoma differentiation associated protein 5, had no effect. In addition, induction of IFN-beta depended on the downstream transcription IFN regulatory factor 3, and on activation of NF-kappaB and MAPK p38. Finally, STING, an endoplasmic reticulum-resident protein, was found to localize in close proximity to the chlamydial inclusion membrane during infection. These results indicate that C. muridarum induces IFN-beta via stimulation of nucleotide-binding oligomerization domain 1 pathway, and TLR- and Rig-I-like receptor-independent pathways that require STING, culminating in activation of IFN regulatory factor 3, NF-kappaB, and p38 MAPK.
 ...
PMID:Stimulator of IFN gene is critical for induction of IFN-beta during Chlamydia muridarum infection. 2010 83

Toll-like receptors (TLRs) are a major family of pattern recognition receptors (PRRs) and play a crucial role in innate immune system. Even though non-receptor spleen tyrosine kinase (Syk) is a key signaling molecule of immunoreceptor tyrosine-based activation motifs-containing immunoreceptors, its role in TLRs signaling is not clearly understood. Herein, we investigated the role of Syk in TLR-mediated signaling and gene regulation. In bone marrow-derived macrophages (BMDMs) and RAW 264.7 macrophages, treatment of poly(I:C), LPS and CpG, which are specific ligands of TLR3, TLR4 and TLR9, respectively, can increase the mRNA levels of several pro-inflammatory cytokines and mediators, including IFNbeta, TNFalpha, MIP2, IL-6, IL-12beta, iNOS and COX-2. The gene upregulation caused by TLR was inhibited by Syk inhibitor (SykI) and JNK inhibitor (SP600125). Accordingly we found the abilities of TLR3, TLR4 and TLR9 ligands to induce Syk and JNK activation, as evidenced by increased Syk autophosphorylation on Y519/Y520, JNK phosphorylation and both kinase activities. We also found that TLRs-mediated JNK activation, but not IKK, p38 and ERK activation as well as IkappaB degradation in BMDM and RAW 264.7 cells, was blocked by SykI. Nevertheless TLR-mediated JNK activation as well as the increased protein expression of iNOS and COX-2 remained unchanged when Syk protein was knockdown by siRNA approach. With in vitro kinase assay we found two commercial Syk inhibitors (SykI, and BAY61-3606) have direct inhibition on JNK activity. These findings demonstrate that the non-selective action of SykI on JNK should be taken into consideration upon using them to explore the biological actions of Syk.
 ...
PMID:Anti-inflammatory actions of Syk inhibitors in macrophages involve non-specific inhibition of toll-like receptors-mediated JNK signaling pathway. 2013 67

Production of chemokines in dendritic cells (DCs) may be crucial in modulating immune responses generated through Toll-like receptor (TLR)-mediated recognition of microbial products. We evaluated chemokine production in DCs induced by TLR agonists and investigated the role of signaling pathways. DCs were generated from mouse bone marrow cells cultured with Fms-like tyrosine kinase-3 ligand and stimulated with a wide array of individual TLR agonists or simultaneously with pairs of combinations. Production of monocyte chemoattractant protein-1 (MCP-1/CCL2), macrophage inflammatory protein-1 (MIP-1/CCL3) and regulated on activation, normal T cell expressed and secreted (RANTES/CCL5), were determined in cell culture supernatants by ELISA or cytokine cytometric bead array. Pharmacological inhibitors of p38 mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), nuclear factor-kappaB (NF-kB) and phosphatidylinositol 3-kinase (PI3K), were used to investigate the role of signaling pathways. TLR agonists induced significantly elevated MCP-1, RANTES, and MIP-1. Production of RANTES and MIP-1 was particularly prominent after stimulation of DCs with TLR3 (Poly(I:C)), and TLR7/8 (R848) or TLR9 (CpG ODN) agonists, respectively. However, down-modulation of chemokine production was observed in simultaneously TLR-stimulated DCs. A positive role was identified for NF-kB, PI3K and ERK, whereas JNK had a negative regulatory effect on chemokine production in DCs. Positive and negative regulatory roles for the p38 MAPK pathway were observed. Thus, chemokine levels differed and most notably there was down-modulation of chemokines in DCs stimulated with combined TLR agonists. Furthermore, analysis of signaling pathways revealed a role for MAPKs in positive and negative regulation of chemokine production in DCs. The chemokine response of DCs induced by TLR agonists appears complex and could have important implications for vaccine design.
 ...
PMID:Regulation of Toll-like receptor-induced chemokine production in murine dendritic cells by mitogen-activated protein kinases. 2045 Dec 53


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>