Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P05412 (c-Jun)
 11,453 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Gram-negative bacteria and the LPS constituent of their outer membranes stimulate the release of inflammatory mediators believed to be responsible for the clinical manifestations of septic shock. The GPI-linked membrane protein, CD14, initiates the signaling cascade responsible for the induction of this inflammatory response by LPS. In this paper, we report the generation and characterization of CD14-null mice in which the entire coding region of CD14 was deleted. As expected, LPS failed to elicit TNF-alpha and IL-6 production in macrophages taken from these animals, and this loss in responsiveness is associated with impaired activation of both the NF-kappaB and the c-Jun N-terminal mitogen-activated protein kinase pathways. The binding and uptake of heat-killed Escherichia coli, measured by FACS analysis, did not differ between CD14-null and wild-type macrophages. However, in contrast to the findings with LPS, whole E. coli stimulated similar levels of TNF-alpha release from CD14-null and wild-type macrophages at a dose of 10 bioparticles per cell. This effect was dose dependent, and at lower bacterial concentrations CD14-deficient macrophages produced significantly less TNF-alpha than wild type. Approximately half of this CD14-independent response appeared to be mediated by CD11b/CD18, as demonstrated by receptor blockade using neutrophil inhibitory factor. An inhibitor of phagocytosis, cytochalasin B, abrogated the induction of TNF-alpha in CD14-deficient macrophages by E. coli. These data indicate that CD14 is essential for macrophage responses to free LPS, whereas other receptors, including CD11b/CD18, can compensate for the loss of CD14 in response to whole bacteria.
 ...
PMID:Divergent response to LPS and bacteria in CD14-deficient murine macrophages. 1103 61

A family of Toll-like receptor (TLR) mediates the cellular response to bacterial cell wall components; murine TLR2 and TLR4 recognize mycoplasmal lipopeptides (macrophage-activating lipopeptides, 2 kDa (MALP-2)) and LPS, respectively. Costimulation of mouse peritoneal macrophages with MALP-2 and LPS results in a marked increase in TNF-alpha production, showing the synergy between TLR2- and TLR4-mediated signaling pathways. Macrophages pretreated with LPS show hyporesponsiveness to the second LPS stimulation, termed LPS tolerance. The LPS tolerance has recently been shown to be primarily due to the down-regulation of surface expression of the TLR4-MD2 complex. When macrophages were treated with MALP-2, the cells showed hyporesponsiveness to the second MALP-2 stimulation, like LPS tolerance. Furthermore, macrophages pretreated with MALP-2 showed reduced production of TNF-alpha in response to LPS. LPS-induced activation of both NF-kappaB and c-Jun NH(2)-terminal kinase was severely impaired in MALP-2-pretreated cells. However, MALP-2-pretreated macrophages did not show any reduction in surface expression of the TLR4-MD2 complex. These findings indicate that LPS-induced LPS tolerance mainly occurs through the down-regulation of surface expression of the TLR4-MD2 complex; in contrast, MALP-2-induced LPS tolerance is due to modulation of the downstream cytoplasmic signaling pathways.
 ...
PMID:Synergy and cross-tolerance between toll-like receptor (TLR) 2- and TLR4-mediated signaling pathways. 1112 Aug 39

Lipopolysaccharide (LPS [endotoxin]) is the principal component of the outer membrane of Gram-negative bacteria. Recent studies have elucidated how LPS is recognized by monocytes and macrophages of the innate immune system. Human monocytes are exquisitely sensitive to LPS and respond by expressing many inflammatory cytokines. LPS binds to LPS-binding protein (LBP) in plasma and is delivered to the cell surface receptor CD14. Next, LPS is transferred to the transmembrane signaling receptor toll-like receptor 4 (TLR4) and its accessory protein MD2. LPS stimulation of human monocytes activates several intracellular signaling pathways that include the IkappaB kinase (IKK)-NF-kappaB pathway and three mitogen-activated protein kinase (MAPK) pathways: extracellular signal-regulated kinases (ERK) 1 and 2, c-Jun N-terminal kinase (JNK) and p38. These signaling pathways in turn activate a variety of transcription factors that include NF-kappaB (p50/p65) and AP-1 (c-Fos/c-Jun), which coordinate the induction of many genes encoding inflammatory mediators.
 ...
PMID:LPS induction of gene expression in human monocytes. 1125 52

Glucocorticoid-attenuated response genes (GARG) belong to a recently described family of genes responsive to the action of dexamethasone. Full-length cDNA of one member of this family, GARG16, has been cloned from rat microglia and regulation of its mRNA expression has been studied. Moreover, regulation of retinoid/retinoic acid activated transcription factor (RXR/RAR) mRNAs in mixed astrocyte and in purified microglia cultures has been investigated. RARbeta mRNA was undetectable in microglia by RT-PCR, whereas clearly present in the mixed cultures. RXRalpha, RARgamma, and GARG16 mRNAs were found in both culture systems. RXRalpha mRNA was strongly expressed in control microglia but rapidly declined upon treatment with LPS. Conversely, GARG16 mRNA was almost untraceable in control microglia but rapidly increased by LPS. Time-course studies revealed an oscillating behavior of expression of both mRNAs during the first 6 hr, which receded to control levels (RXRalpha high, GARG16 low) at 72 hr of LPS-treatment. Additionally, p38 MAPK and SEK phosphorylations peaked at 1 hr followed by steady declines, whereas MEK and c-Jun showed double peaks at 1+4 hr and 1+6 hr, respectively, before subsiding to control levels. This behavior was not observed in comparative studies with TNF-alpha, interleukin-10 (IL-10), or interferon-gamma inducible protein 10 (IP-10). Finally, inhibitors of p38 MAPK, p42/p44 ERK, and PKCalpha as well as the use of dexamethasone revealed major influences of the p38 MAPK-c-Jun-AP-1 signaling pathway on RXRalpha and GARG16 mRNA expressions. The counter regulatory control of GARG16 and RXRalpha mRNA expression is believed to be an example of a fine-tuned cellular mechanism to react to inflammatory stimuli.
 ...
PMID:Lipopolysaccharide-induced switch between retinoid receptor (RXR) alpha and glucocorticoid attenuated response gene (GARG)-16 messenger RNAs in cultured rat microglia. 1139 78

Toll-like receptors (TLRs) are mammalian homologues of the Drosophila Toll receptors and are thought to have roles in innate recognition of bacteria. We demonstrated that TLR 2, 4, 6, and 8 but not TLR5 were expressed on mouse bone marrow-derived mast cells (BMMCs). Using BMMCs from the genetically TLR4-mutated strain C3H/HeJ, we demonstrated that functional TLR4 was required for a full responsiveness of BMMCs to produce inflammatory cytokines (IL-1beta, TNF-alpha, IL-6, and IL-13) by LPS stimulation. TLR4-mediated stimulation of mast cells by LPS was followed by activation of NF-kappaB but not by stress-activated protein kinase/c-Jun NH2-terminal kinase signaling. In addition, in the cecal ligation and puncture-induced acute septic peritonitis model, we demonstrated that genetically mast cell-deficient W/W(v) mice that were reconstituted with TLR4-mutated BMMCs had significantly higher mortality than W/W(v) mice reconstituted with TLR4-intact BMMCs. Higher mortality of TLR4-mutated BMMC-reconstituted W/W(v) mice was well correlated with defective neutrophil recruitment and production of proinflammatory cytokines in the peritoneal cavity. Taken together, these observations provide definitive evidence that mast cells play important roles in exerting the innate immunity by releasing inflammatory cytokines and recruitment of neutrophils after recognition of enterobacteria through TLR4 on mast cells.
 ...
PMID:Protective roles of mast cells against enterobacterial infection are mediated by Toll-like receptor 4. 1149 12

The vasoactive intestinal peptide (VIP) and the pituitary adenylate cyclase-activating polypeptide (PACAP), two immunomodulatory neuropeptides, act as anti-inflammatory factors for activated microglia, by inhibiting the production of proinflammatory factors. In the present study the effects of VIP/PACAP on the MEKK1/MEK4/JNK transduction pathway and on the subsequent changes in Jun family members, a transduction pathway clearly involved in the activation of microglia cells were examined. VIP/PACAP inhibit MEKK1 activity and the subsequent phosphorylations of MEK4, JNK, and c-Jun, which result in a decrease in the AP-1 binding and a marked change in the composition of AP-1 complexes from c-Jun/c-Fos to JunB/c-Fos. Furthermore, VIP stimulates JunB production in LPS-stimulated microglia. Both inhibition of the MEKK1/MEK4/JNK pathway, leading to a reduction in phosphorylated c-Jun, and the stimulation of JunB are mediated through the specific VPAC1 receptor and cAMP/PKA pathway. The VIP/PACAP interference with the stress-induced SAPK/JNK pathway in activated microglia may represent a significant element in the regulation of inflammatory response in the CNS by endogenous neuropeptides.
 ...
PMID:Vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide inhibit the MEKK1/MEK4/JNK signaling pathway in endotoxin-activated microglia. 1205 37

Heat shock response has been implicated in cytoprotective effects from cellular damage and in the regulation of cytokine expression. We report the effect of heat shock on LPS-induced expression of IL-18, an important cytokine that has diverse immune regulatory effects on T cells, B cells, NK cells, and nonimmune cells. The augmentation of LPS-induced IL-18 mRNA and protein was significantly suppressed in murine peritoneal macrophages after 43 degrees C heat shock treatment. In addition, the JNK MAPK inhibitor SP600125 inhibited IL-18 mRNA transcription in a dose-dependent manner. To examine the possibility that the inhibition of IL-18 may be mediated through the inactivation of JNK, the activity of JNK was measured by using Western blot and kinase assays. Our data show that heat shock response decreased LPS-induced phosphorylation of JNK and its downstream substrate c-Jun. AP-1, a transcriptional factor composed of c-Jun, could regulate the expression of IL-18. Also, its DNA-binding activity was reduced by the heat shock response. These findings suggest that treatment of heat stress results in inhibition of IL-18 production in macrophages mainly through the JNK/AP-1 signaling pathway.
 ...
PMID:Heat shock response inhibits IL-18 expression through the JNK pathway in murine peritoneal macrophages. 1217 45

Inflammatory mediators such as TNF and bacterial LPS do not cause significant apoptosis of endothelial cells unless the expression of cytoprotective genes is blocked. In the case of TNF, the transcription factor NF-kappaB conveys an important survival signal. In contrast, even though LPS can also activate NF-kappaB, this signal is dispensable for LPS-inducible cytoprotective activity. LPS intracellular signals are transmitted through a member of the Toll-like receptor family, TLR4. This family of receptors transduces signals through a downstream molecule, TNFR-associated factor 6 (TRAF6). In this study, we demonstrate that the C-terminal fragment of TRAF6 (TRAF6-C) inhibits LPS-induced NF-kappaB nuclear translocation and c-Jun NH(2)-terminal kinase (JNK) activation in endothelial cells. In contrast, LPS activation of p38 kinase is not inhibited by TRAF6-C. TRAF6-C also inhibits LPS-initiated endothelial apoptosis, but potentiates TNF-induced apoptosis. LPS-induced loss of mitochondrial transmembrane potential, cytochrome c release, and caspase activation are all blocked by TRAF6-C. We demonstrate that TRAF6 signals apoptosis via JNK activation, since inhibition of JNK activation using a dominant-negative mutant also inhibits apoptosis. JNK inhibition blocks caspase activation, but the reverse is not true. Hence, JNK activation lies upstream of caspase activation in response to LPS stimulation.
 ...
PMID:Lipopolysaccharide signals an endothelial apoptosis pathway through TNF receptor-associated factor 6-mediated activation of c-Jun NH2-terminal kinase. 1219 32

The c-Jun N-terminal kinases (JNKs) exert a pleiotrophy of physiological and pathological actions. This is also true for the immune system. Disruption of the JNK locus results in substantial functional deficits of peripheral T-cells. In contrast to circulating immune cells and the role of p38, the presence and function of JNKs in the immune cells of the brain remain to be defined. Here, we report on the expression and activation of JNKs in cultivated microglia from neonatal rats and from mice with targeted disruption of the JNK locus and the N-terminal mutation of c-Jun (c-JunAA), respectively. JNK1, 2 and 3 mRNA and proteins were all expressed in microglia. Following stimulation with LPS (100 ng/mL), a classical activator of microglia, JNKs were rapidly activated and this activation returns to basal levels within 4 hr. Following LPS and other stimuli such as thrombin (10-50 unit/mL), the activation of JNKs went along with the N-terminal phosphorylation of c-Jun which persisted for at least 8 hr. Indirect inhibition of JNK by CEP-11004 (0.5-2 microM), an inhibitor of mixed-lineage kinases (MLK), reduced the LPS-induced phosphorylation of both, JNK and c-Jun, by around 50%, and attentuated the LPS-induced the alterations in microglial morphology. Finally, JNKs are involved in the control of cytokine release since both, incubation with CEP-11004 and disruption of the JNK1 locus enhanced the release of TNFalpha, IL-6 and IL-12. Our findings provide insight in so far unknown functions of JNKs in cerebral immune cells. These observations are also important for the wide spread efforts to develop JNK-inhibitors as neuroprotective drugs which, however, might trigger pro-inflammatory processes.
 ...
PMID:The c-Jun N-terminal kinases in cerebral microglia: immunological functions in the brain. 1221 70

Exposure of macrophages to LPS induces a state of hyporesponsiveness to subsequent challenge with LPS. It has not been known whether previous exposure to CpG DNA induces a similar suppressive response to subsequent stimulation with CpG DNA. In the present study, we demonstrate that pretreatment with CpG DNA induces suppression of cytokine release in a murine macrophage-like cell RAW264.7 in response to subsequent challenge by CpG DNA. Additionally, CpG DNA-mediated activation of mitogen-activated protein kinases, including c-Jun NH(2)-terminal kinase, extracellular signal-regulated kinase, and p38, and activation of transcription factors AP-1, CREB, NF-kappaB, and STAT1 are greatly suppressed in the cells pre-exposed to CpG DNA. Pretreatment with CpG DNA also partially inhibited LPS-mediated production of cytokines and activation of mitogen-activated protein kinases and transcription factors. Neither LPS nor CpG DNA treatment inhibited Toll-like receptor 4, MD2, Toll-like receptor 9, myeloid differentiation factor 88, Toll/IL-1R domain-containing adaptor protein, Tollip, and TNF-alpha receptor-associated factor 6 expression. Interestingly, CpG DNA or LPS stimulation led to the inhibition of IL-1R-associated kinase expression. These results indicate that CpG DNA-induced refractory of RAW264.7 cells may be, at least in part, due to suppressed IL-1R-associated kinase expression.
 ...
PMID:CpG DNA induces self and cross-hyporesponsiveness of RAW264.7 cells in response to CpG DNA and lipopolysaccharide: alterations in IL-1 receptor-associated kinase expression. 1251 73


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