Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P10145 (IL-8)
 23,849 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Central to the pathogenesis of Salmonella typhimurium is its ability to engage the host cell in a two-way biochemical interaction. As a consequence of this interaction, a dedicated protein secretion system, termed type III, is activated in these bacteria and directs the translocation of signaling proteins into the host cell. Secretion of these proteins stimulates host cell signal transduction pathways that lead to a variety of cellular responses. An important feature of S. typhimurium pathogenesis is the induction of a profound inflammatory response in the intestinal epithelium. In this report, we show that S. typhimurium induces host cell signal transduction pathways that lead to the activation of the transcription factors NF-kappaB and AP-1, resulting in the production of proinflammatory cytokines such as IL-8. We also show that S. typhimurium infection of cultured intestinal epithelial cells results in the activation of the mitogen-activated protein (MAP) kinases ERK, JNK, and p38. Induction of these signaling pathways and the synthesis of IL-8 was strictly dependent on the function of the invasion-associated type III protein secretion system encoded by S. typhimurium. Pretreatment of cells with the highly specific p38 MAP kinase inhibitor SB 203580 prevented S. typhimurium-induced IL-8 production. These results indicate that the inflammatory response induced by S. typhimurium may be due to the specific stimulation of MAP kinase signaling pathways leading to nuclear responses.
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PMID:Involvement of mitogen-activated protein kinase pathways in the nuclear responses and cytokine production induced by Salmonella typhimurium in cultured intestinal epithelial cells. 954 96

NF-kappa B plays a critical role in the transcriptional regulation of proinflammatory gene expression in various cells. Cytokine-mediated activation of NF-kappa B requires activation of various kinases, which ultimately leads to the phosphorylation and degradation of I kappa B, the NF-kappa B cytoplasmic inhibitor. The food derivative curcumin has been shown to inhibit NF-kappa B activity in some cell types. In this report we investigate the mechanism of action of curcumin on cytokine-induced proinflammatory gene expression using intestinal epithelial cells (IEC). Curcumin inhibited IL-1 beta-mediated ICAM-1 and IL-8 gene expression in IEC-6, HT-29, and Caco-2 cells. Cytokine-induced NF-kappa B DNA binding activity, RelA nuclear translocation, I kappa B alpha degradation, I kappa B serine 32 phosphorylation, and I kappa B kinase (IKK) activity were blocked by curcumin treatment. Wound-induced p38 phosphorylation was not inhibited by curcumin treatment. In addition, mitogen-activated protein kinase/ERK kinase kinase-1-induced IL-8 gene expression and 12-O-tetraphorbol 12-myristate 13-acetate-responsive element-driven luciferase expression were inhibited by curcumin. However, I kappa B alpha degradation induced by ectopically expressed NF-kappa B-inducing kinase or IKK was not inhibited by curcumin treatment. Therefore, curcumin blocks a signal upstream of NF-kappa B-inducing kinase and IKK. We conclude that curcumin potently inhibits cytokine-mediated NF-kappa B activation by blocking a signal leading to IKK activity.
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PMID:Curcumin blocks cytokine-mediated NF-kappa B activation and proinflammatory gene expression by inhibiting inhibitory factor I-kappa B kinase activity. 1047 20

Adhesion of human monocytes (MOs) results in the rapid transcriptional activation of cytokine genes that are dependent on nuclear factor (NF)-kappaB. Several pathways leading to activation of NF-kappaB have been described, including those involving reactive oxygen intermediates (ROIs) and members of the mitogen-activated protein (MAP) kinase superfamily. To investigate the involvement of tyrosine phosphorylation (TP) and oxidant generation in interleukin (IL)-8 and GRO messenger RNA induction, MOs and human alveolar macrophages (AMs) were adhered to plastic or exposed to a particulate pollutant, residual oil fly ash (ROFA). Both stimuli caused rapid TP and ROI production in MOs and AMs. However, neither NF-kappaB translocation nor IL-8 gene induction occurred in adhered or ROFA-exposed AMs. Analysis of MAP kinase activation found phosphorylation of Jun amino-terminal kinase (JNK) and p38 in the AMs, but not of extracellular regulated kinase/MAP kinase (ERK/MAPK). AMs stimulated with lipopolysaccharide activated ERK/MAPK, in addition to JNK and p38, and showed translocation of NF-kappaB. In contrast to AMs, MO adhesion or exposure to ROFA particles in suspension rapidly activated p38, JNK, and ERK/MAPK, and activated NF-kappaB binding as well as IL-8 mRNA expression. Pretreatment with the tyrosine kinase inhibitors genistein or herbimycin A before adherence had no effect on transcriptional activation in MOs, whereas adherence and ROFA-induced oxidant generation was inhibited in both MOs and AMs. Taken together, these data indicate that NF-kappaB activation or generalized transcriptional activation of cytokine genes are independent of changes in oxidant stress imposed on phagocytes by adhesion. Furthermore, the data suggest that certain environmental responses in AMs may be uncoupled from activation of NF-kappaB.
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PMID:Adhesion and pollution particle-induced oxidant generation is neither necessary nor sufficient for cytokine induction in human alveolar macrophages. 1065 41

Monocyte adhesion resulted in rapid tyrosine phosphorylation and subsequent cytokine mRNA induction. The objective of this study was to determine the role of specific tyrosine phosphorylation events, particularly those involving members of the MAP kinase family, in regulating adhesion-induced cytokine expression. Using nuclear run-on analyses, we demonstrated that on adhesion, monocytes rapidly transcriptionally activated numerous cytokine mRNAs, coincident with the activation of the transcription factors NF-KB and AP-1. Both an inhibitor of tyrosine phosphorylation, genistein, and the cytoplasmic tyrosine phosphatase PTP1B, were unable to prevent adhesion-mediated transcriptional activation. However, both blocked adhesion-induced ERK and JNK but not p38 kinase activation and at the same time decreased the stability of interleukin-1beta (IL-1beta) and IL-8 transcripts. In addition, whereas adhesive events occurred in the presence of genistein and PTP1B, monocyte spreading was markedly inhibited. Our results suggest that the majority of protein phosphorylation events are associated with adhesion-induced cytokine expression through transcript stabilization and cytoskeletal organization. A minority of protein phosphorylation events, not sensitive to genistein or PTP1B exposure, may be instrumental in regulating transcription. Thus the spectrum of protein tyrosine kinases required for transcription appear distinct from those involved in maintaining the stability of some cytokine mRNAs and the integrity of the cytoskeleton to which mRNA destined for translation must be associated.
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PMID:Differential role of tyrosine phosphorylation in adhesion-induced transcription, mRNA stability, and cytoskeletal organization in human monocytes. 1067 May 83

Eosinophils, the major immune effector cells contributing to allergic inflammation and asthma, are profoundly affected by interleukin (IL) 5 with respect to their differentiation, viability, recruitment, and cytotoxic effector functions. IL-5 enhances eosinophil responsiveness to a variety of chemotactic factors via a process called priming, although the molecular mechanism is unknown. In this study, we report that, following IL-5 priming of eosinophils, chemotactic agents including fMet-Leu-Phe, IL-8, and RANTES, promote vigorous transient activation of ERK1 and ERK2. In contrast, these chemotactic factors stimulate weak or indiscernible ERK activation in unprimed eosinophils. Furthermore, this intracellular marker of priming is selective for IL-5-related cytokines, in that it is observed following exposure to IL-5 and granulocyte macrophage-colony stimulating factor but not to interferon-gamma, stem cell factor, tumor necrosis factor alpha, or IL-4. Interestingly, priming of chemoattractant-induced ERK activation is accompanied by an increase in association of tyrosine-phosphorylated proteins with the adapter protein Grb2. The biological relevance of ERK activation to IL-5 priming is supported by the observation that inhibition of ERK activity by treatment with the MEK inhibitors PD98059 or U0126 inhibited the release of leukotriene C(4) stimulated by fMet-Leu-Phe in IL-5-primed eosinophils. These data provide evidence for a previously undescribed fundamental mechanism by which stimulation of IL-5 family receptors induces a rapid phenotypic alteration in the signal transduction pathways of chemotactic receptors, enabling their activation of the ERK1 and ERK2 pathway and contributing to the capacity of these cells to synthesize LTC(4).
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PMID:ERK1 and ERK2 activation by chemotactic factors in human eosinophils is interleukin 5-dependent and contributes to leukotriene C(4) biosynthesis. 1075 97

Bradykinin (BK) is a major kinin with well-documented pharmacological properties including vascular leakage and induction of a variety of cytokines. However, the intracellular signalling mechanisms by which BK induced proinflammatory cytokine production have not been fully elucidated. This study investigated the role of the extracellular signal-regulated protein kinase 1/2 (ERK 1/2) and p38 mitogen-activated protein kinase (p38 MAPK) in the BK-induced interleukin (IL)-6 and IL-8 production by human lung fibroblasts. Lung fibroblasts were stimulated with BK in the presence or in the absence of PD98059, a specific MAPK/ERK kinase-1 inhibitor, or SB203580, a specific p38 MAPK inhibitor, and IL-6 or IL-8 production and their gene expression was examined. BK-induced ERK 1/2 or p38 MAPK phosphorylation was also analysed by Western blot analysis. BK at nanomolar concentrations stimulated lung fibroblasts to produce IL-6 and IL-8 along with increased ERK 1/2 and p38 MAPK phosphorylation. BK-induced IL-6 and IL-8 synthesis was inhibited by a B2-type BK receptor antagonist. Furthermore, PD98059 or SB203580 significantly suppressed BK-induced IL-6 and IL-8 production and their gene expression. These results indicate that bradykinin-induced interleukin-6 and interleukin-8 production are at least partly mediated through the extracellular signal-related protein kinase 1/2 and p38 mitogen-activated protein kinase pathway-dependent activation in human lung fibroblasts, and suggest that bradykinin appears to be involved in the inflammatory reaction leading to acute lung injury through stimulating interleukin-6 and interleukin-8 production by lung fibroblasts.
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PMID:Bradykinin stimulates IL-6 and IL-8 production by human lung fibroblasts through ERK- and p38 MAPK-dependent mechanisms. 1102 59

Chemokines constitute a superfamily of proteins that function as chemoattractants and activators of leukocytes. Astrocytes, the major glial cell type in the CNS, are a source of chemokines within the diseased brain. Specifically, we have shown that primary human astrocytes and human astroglioma cell lines produce the CXC chemokines IFN-gamma-inducible protein-10 and IL-8 and the CC chemokines monocyte chemoattractant protein-1 and RANTES in response to stimuli such as TNF-alpha, IL-1beta, and IFN-gamma. In this study, we investigated chemokine receptor expression and function on human astroglioma cells. Enhancement of CXC chemokine receptor 4 (CXCR4) mRNA expression was observed upon treatment with the cytokines TNF-alpha and IL-1beta. The peak of CXCR4 expression in response to TNF-alpha and IL-1beta was 8 and 4 h, respectively. CXCR4 protein expression was also enhanced upon treatment with TNF-alpha and IL-1beta (2- to 3-fold). To study the functional relevance of CXCR4 expression, stable astroglioma transfectants expressing high levels of CXCR4 were generated. Stimulation of cells with the ligand for CXCR4, stromal cell-derived factor-1alpha (SDF-1alpha), resulted in an elevation in intracellular Ca(2+) concentration and activation of the mitogen-activated protein kinase cascade, specifically, extracellular signal-regulated kinase 2 (ERK2) mitogen-activated protein kinase. Of most interest, SDF-1alpha treatment induced expression of the chemokines monocyte chemoattractant protein-1, IL-8, and IFN-gamma-inducible protein-10. SDF-1alpha-induced chemokine expression was abrogated upon inclusion of U0126, a pharmacological inhibitor of ERK1/2, indicating that the ERK signaling cascade is involved in this response. Collectively, these data suggest that CXCR4-mediated signaling pathways in astroglioma cells may be another mechanism for these cells to express chemokines involved in angiogenesis and inflammation.
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PMID:CXC chemokine receptor 4 expression and function in human astroglioma cells. 1116 Mar 34

Exposure to fluorides can induce inflammatory reactions, cell cycle arrest, and apoptosis in different experimental systems. Fluorides are known G-protein activators, but less is known about fluoride effects downstream of G-protein activation. The aim of this study was to elucidate whether the induction of apoptosis by fluorides and inhibition of proliferation is mediated by MAP kinases in primary rat lung, alveolar type 2 cells and the human epithelial lung cell line A549. Sodium fluoride (NaF) induced apoptosis in both cell types but at different concentrations, with the primary cells being more sensitive to NAF: Proliferation of the type 2 cells and A549 cells was inhibited in the presence of NAF: NaF induced a prolonged activation of MAP kinase ERK. NaF also activated p38 and JNK in A549 cells for several hours (maximally 6-fold and 3-fold increase, respectively). Inhibition of ERK with the MEK1,2 inhibitor PD98059 increased apoptosis 2-fold, whereas the inhibitor of p38, SB202190, decreased the level of apoptotic cells by approximately 40%. SB202190 also inhibited apoptosis by almost 40% when ERK activity was reduced in the presence of PD98059. Neither PD98059 nor SB202190 did affect the NaF-induced inhibition of proliferation. These observations indicate that activation of MAP kinases p38 and possibly JNK are involved in NaF-induced apoptosis of epithelial lung cells, whereas ERK activation seems to counteract apoptosis in epithelial lung cells. In contrast, activation of ERK and p38 are not involved in NaF-induced inhibition of cell proliferation.
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PMID:Fluoride-induced apoptosis in epithelial lung cells involves activation of MAP kinases p38 and possibly JNK. 1129 78

1. Recent data indicate that interleukin (IL)-17 may contribute to neutrophilic airway inflammation by inducing the release of neutrophil-mobilizing cytokines from airway cells. The aim of this study was to evaluate the role of mitogen activated protein kinases in IL-17 induced release of IL-8 and IL-6 in bronchial epithelial cells. 2. Transformed human bronchial epithelial cells (16HBE) were stimulated with either IL-17 or vehicle. Both groups were treated either with SB202190 (inhibitor of p38 MAP kinase), PD98059 (inhibitor of extracellular-signal-regulated kinase [ERK] pathway), Ro-31-7549 (protein kinase C [PKC] inhibitor), LY 294002 (a phosphatidylinositol 3-kinase [PI 3-kinase] inhibitor) or vehicle. IL-6 and IL-8 levels were measured in conditioned media by ELISA. 3. The IL-17-induced release of IL-6 and IL-8 was concentration-dependently inhibited by SB202190 and by PD98059 in bronchial epithelial cells without affecting cell proliferation or survival. 4. Ro-31-7549 and LY294002 had no significant effect on IL-17-induced IL-6 or IL-8 release in bronchial epithelial cells. 4. Taken together, these data indicate a role for p38 and ERK kinase pathways in IL-17-induced release of neutrophil-mobilizing cytokines in human bronchial epithelial cells. These mechanisms constitute potential pharmacotherapeutical targets for inhibition of the IL-17-mediated airway neutrophilia.
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PMID:IL-17-induced cytokine release in human bronchial epithelial cells in vitro: role of mitogen-activated protein (MAP) kinases. 1132 11

Sodium fluoride (NaF) has previously been reported to induce a strong IL-8 response in human epithelial lung cells (A549) via mechanisms that seem to involve the activation of G proteins. In the present study the signal pathways downstream of the G proteins have been examined. NaF induced a weak, but sustained increase in PKC activity. In contrast, the PKC activator TPA induced a relatively strong, but transient effect and augmented the NaF-induced PKC activity. TPA induced a marked IL-8 response compared to NaF. PDB, another PKC activator, was less effective, but augmented the IL-8 response to NaF. Pretreatment with TPA for 20 h, or the PKC inhibitor GF109203X for 1 h, abolished the basal and NaF-induced PKC activities and partially prevented the NaF-induced IL-8 response. Inhibition of the MAP kinase p38 by SB202190 partially reduced the IL-8 response to NaF, whereas a reduction in ERK activity by PD98059 led to an increased response. The NaF-induced IL-8 response was weakly augmented by the PKA stimulator forskolin and the G(i) inhibitor pertussis toxin. The PKA inhibitor H89 seemed to reduce the NaF-induced IL-8 response, but the measured effect was not statistically significant. BAPTA-AM, KN93 and W7, that inhibit Ca(2+)-linked effects, did not affect the IL-8 response. Furthermore, the tyrosine kinase inhibitor genestein, the PI-3 kinase inhibitor wortmannin and phosphatase inhibition were without effects. In conclusion, the data suggest that NaF-induced increase of IL-8 in A549 cells involved PKC- and p38-linked pathways, whereas an ERK-dependent pathway counteracted the response. Tyrosine kinases, Ca(2+)-linked pathways, PI-3 kinase, PKA and phosphatase inhibition seem to play no or minor roles in the fluoride-induced IL-8 response.
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PMID:Mechanisms in fluoride-induced interleukin-8 synthesis in human lung epithelial cells. 1156 78


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