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)

We examined the effects of different bacterial doses of Neisseria gonorrhoeae on the cytokine response of primary human monocytes. The data indicate that a low multiplicity of infection (MOI) challenge (MOI = 0.1) results in substantial production of IL-8 and other chemokines/cytokines, in the absence of significant TNF-alpha production. Positive control challenges (MOI = 10) induced levels of IL-8 that were comparable to the low MOI challenges, but now induced significant levels of TNF-alpha. Induction of IL-8 expression in low MOI challenges was not mediated by an autocrine response as pretreatment of monocytes with neutralizing Abs against TNF-alpha or IL-1beta had no effect on IL-8 expression. IL-8 induction resulting from gonococcal challenge was shown to require NF-kappaB activation, though this activation was limited by the inoculating dose. These data indicate that IL-8 induction results from direct contact between bacteria and monocytes. Analysis of the overall cytokine profile revealed patterns of expression for growth-regulated oncogene, MCP-1, and IL-6 that were similar to IL-8. Analysis of various MAPKs indicated that low MOI challenges were able to efficiently activate both the ERK and p38 pathways, but in contrast to positive control samples, failed to activate the JNK pathway. A lack of phosphorylated JNK leads to decreased production of AP-1 dimers, transcription factors that are critical for efficient transcription of TNF-alpha. Therefore, we propose a mechanism where a low MOI gonococcal challenge results in diminished AP-1 activity and TNF-alpha production while IL-8 levels remain constant.
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PMID:TNF-alpha-independent IL-8 expression: alterations in bacterial challenge dose cause differential human monocytic cytokine response. 1681 92

Histone deacetylase (HDAC) inhibitors are appreciated as one of promising anticancer drugs, but they exert differential responses depending on the cell type. We recently reported the critical role of NF-kappaB as a modulator in determining cell fate for apoptosis in response to an HDAC inhibitor. In this study, we investigate a possible signaling pathway required for NF-kappaB activation in response to the HDAC inhibitor apicidin. Treatment of HeLa cells with apicidin leads to an increase in transcriptional activity of NF-kappaB and the expression of its target genes, IL-8 and TNF-alpha. TNF-alpha expression by apicidin is induced at earlier time points than NF-kappaB activation or IL-8 expression. In addition, our data show that the early expression of TNF-alpha does not lead to activation of NF-kappaB, because disruption of TNF-alpha activity by a neutralizing antibody does not affect nuclear translocation of NF-kappaB, IkappaBalpha degradation or reporter gene activation by apicidin. However, this activation of NF-kappaB requires the PI3K and PKC signaling pathways, but not ERK or JNK. Furthermore, apicidin activation of NF-kappaB seems to result from HDAC1 inhibition, as evidenced by the observation that overexpression of HDAC1, but not HDAC2, 3 or 4, dramatically inhibits NF-kappaB reporter gene activity. Collectively, our results suggest that activation of NF-kappaB signaling by apicidin requires both the PI3K/PKC signaling pathways and HDAC1, and functions as a critical modulator in determining the cellular effect of apicidin.
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PMID:Involvement of HDAC1 and the PI3K/PKC signaling pathways in NF-kappaB activation by the HDAC inhibitor apicidin. 1687 Jan 49

Pathogenic Yersinia species share a type III secretion system that translocates Yop effector proteins into host cells to counteract signalling responses during infection. Two of these effectors, YopE and YopT, downregulate Rho GTPases by different mechanisms. Here, we investigate whether YopT and YopE are functionally redundant by dissecting the contribution of these two effectors to the pathogenesis of Yersinia pseudotuberculosis in a mouse infection and tissue culture model. Four days after oral infection, a YopE(+) T (-) strain and a YopE(+) T (+) strain colonized spleens of mice at similar levels, suggesting that YopT is not required for virulence. In contrast, spleen colonization by a YopE(-)T(-) strain was significantly reduced. A YopE(-) T (+) strain colonized spleen at levels comparable to those of the YopE(+) T (-) strain, arguing that YopT can promote virulence in the absence of YopE. Infection of HeLa cells with a YopE(-) T(-)H(-)J(-) strain expressing either YopE or YopT showed that YopE had a stronger antiphagocytic activity than YopT. Expression of YopE strongly inhibited activation of JNK, ERK and NFkappaB, and prevented production of IL-8; whereas YopT moderately inhibited these responses. On the other hand, pore formation was inhibited equally by YopE or YopT. In conclusion, YopE is a potent inhibitor of infection-induced signalling cascades, and YopT can only partially compensate for the loss of YopE.
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PMID:Comparison of YopE and YopT activities in counteracting host signalling responses to Yersinia pseudotuberculosis infection. 1692 68

Mast cells are involved in many disorders where the triggering mechanism that leads to degranulation and/or cytokine secretion has not been defined. Several chronic inflammatory diseases are associated with increased mast cell numbers and upregulation of the TNF receptor family member CD30, but the role of elevated CD30 expression is poorly understood. Here we report what we believe to be a novel way to activate mast cells with CD30 that leads to degranulation-independent secretion of chemokines. CD30 induced a de novo synthesis and secretion of the chemokines IL-8, macrophage inflammatory protein-1alpha (MIP-1alpha), and MIP-1beta, a process involving the MAPK/ERK pathway. Mast cells were found to be the predominant CD30 ligand-positive (CD30L-positive) cell in the chronic inflammatory skin diseases psoriasis and atopic dermatitis, and both CD30 and CD30L expression were upregulated in lesional skin in these conditions. Furthermore, the number of IL-8-positive mast cells was elevated both in psoriatic and atopic dermatitis lesional skin as well as in ex vivo CD30-treated healthy skin organ cultures. In summary, characterization of CD30 activation of mast cells has uncovered an IgE-independent pathway that is of importance in understanding the entirety of the role of mast cells in diseases associated with mast cells and CD30 expression. These diseases include Hodgkin lymphoma, atopic dermatitis, and psoriasis.
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PMID:Mast cell CD30 ligand is upregulated in cutaneous inflammation and mediates degranulation-independent chemokine secretion. 1696 9

Recent improvements in immunohistochemistry panels used for differentiating ovarian serous carcinoma/primary peritoneal carcinoma (OC/PPC) from diffuse malignant peritoneal mesothelioma (DMPM) have resulted in improved diagnostic rates for these tumors in both cytological and histological material. However, little is known about the biological characteristics that differentiate these two cancer types. We performed a comparative analysis of cancer-associated molecule expression data for a cohort consisting of up to 270 serous OC/PPC specimens (only peritoneal lesions) and 32 peritoneal MM. The molecules studied were nerve growth factor receptors (p75, p-TrkA), angiogenic factors (VEGF, IL-8, bFGF, heparanase), laminin receptors (the 67-kDa receptor and the alpha 6 integrin subunit), proteases (MMP-2), immune response mediators (HLA-G), and signaling molecules (the MAPK members ERK, JNK, and p38). The methods used were immunohistochemistry, Western blotting, and RT-PCR. DMPM specimens showed significantly higher expression of p75 (P < 0.001), p-TrkA (P < 0.001), and bFGF (P < 0.001), and significantly lower expression of the 67-kDa receptor (P < 0.001), alpha 6 integrin subunit (P = 0.025), VEGF (P < 0.001), IL-8 (P < 0.001), and HLA-G (P = 0.039) compared with OC/PPC. DMPM specimens showed higher activation ratio (phosphorylated/total enzyme ratio) of all three MAPK members (ERK, P = 0.017; JNK, P < 0.001; p38, P = 0.009) compared with OC/PPC. These data document significant differences in the expression of cancer- and metastasis-associated molecules in MM compared with ovarian carcinoma, and suggest that different biological pathways are involved in tumorigenesis and disease progression in these two tumors.
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PMID:The biological differences between ovarian serous carcinoma and diffuse peritoneal malignant mesothelioma. 1704 94

Among the several effectors that mediate TNF-alpha action is AP-1, which consists of transcription factors belonging to the JUN and FOS families. Although the effects of TNF-alpha in immune cells, such as the induction of NF-kappaBeta, are well known, the mechanisms by which it induces transcriptional activation of AP-1 in pulmonary epithelial cells are not well defined. In this study, we report that TNF-alpha stimulates the expression of the FRA-1 protooncogene in human pulmonary epithelial cells using c-Jun, acting via a 12-O-tetradecanoylphorbol-13 acetate response element located at -318. Although TNF-alpha stimulates phosphorylation of c-Jun, the inhibition of JNK activity had no significant effect on FRA-1 induction. Consistent with this result, ectopic expression of a c-Jun mutant lacking JNK phosphorylation sites had no effect on the TNF-alpha-induced expression of the promoter. In contrast, inhibition of the ERK pathway or ectopic expression of an ERK1 mutant strikingly reduced FRA-1 transcription. ERK inhibition not only blocked phosphorylation of Elk1, CREB, and ATF1, which constitutively bind to the FRA-1 promoter, but also suppressed the recruitment of c-Jun to the promoter. We found that short interfering RNA-mediated silencing of FRA-1 enhances TNF-alpha-induced IL-8 expression, whereas overexpression causes an opposite effect. Our findings collectively indicate that ERK signaling plays key roles in both Elk1, CREB, and ATF-1 activation and the subsequent recruitment of c-Jun to the FRA-1 promoter in response to TNF-alpha in pulmonary epithelial cells.
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PMID:A JNK-independent signaling pathway regulates TNF alpha-stimulated, c-Jun-driven FRA-1 protooncogene transcription in pulmonary epithelial cells. 1708 37

Heat shock protein (HSP) 27 has long been known to be a component of the p38 mitogen-activated protein kinase (MAPK) signaling pathway. p38 MAPK has important functions in the inflammatory response, but the role of HSP27 in inflammation has remained unknown. We have used small interfering RNAs to suppress HSP27 expression in HeLa cells and fibroblasts and found that it is required for pro-inflammatory cell signaling and the expression of pro-inflammatory genes. HSP27 is needed for the activation by interleukin (IL)-1 of TAK1 and downstream signaling by p38 MAPK, JNK, and their activators (MKK-3, -4, -6, -7) and IKKbeta. IL-1-induced ERK activation appears to be independent of HSP27. HSP27 is required for both IL-1 and TNF-induced signaling pathways for which the most upstream common signaling protein is TAK1. HSP27 is also required for IL-1-induced expression of the pro-inflammatory mediators, cyclooxygenase-2, IL-6, and IL-8. HSP27 functions to drive cyclooxygenase-2 and IL-6 expression by augmenting the activation of the kinase downstream of p38 MAPK, MK2, resulting in stabilization of cyclooxygenase-2 and IL-6 mRNAs. The mechanism may not occur in cells of myeloid lineage because HSP27 protein was undetectable in human monocytes and murine macrophages.
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PMID:Heat shock protein 27 functions in inflammatory gene expression and transforming growth factor-beta-activated kinase-1 (TAK1)-mediated signaling. 1720 47

CXCL8 (interleukin-8) interacts with two receptors, CXCR1 and CXCR2, to activate leukocytes. Upon activation, CXCR2 internalizes very rapidly relative to CXCR1 ( approximately 90% versus approximately 10% after 5 min). The C termini of the receptors have been shown to be necessary for internalization but are not sufficient to explain the distinct kinetics of down-regulation. To determine the structural determinant(s) that modulate receptor internalization, various chimeric and point mutant receptors were generated by progressively exchanging specific domains or amino acids between CXCR1 and CXCR2. The receptors were stably expressed in rat basophilic leukemia 2H3 cells and characterized for receptor binding, intracellular Ca(2+) mobilization, phosphoinositide hydrolysis, phosphorylation, internalization, and MAPK activation. The data herein indicate that the second extracellular loop (2ECL) of the receptors is critical for the distinct rate of internalization. Replacing the 2ECL of CXCR2 with that of CXCR1 (B(2ECL)A) or Asp(199) with its CXCR1 valine counterpart (B(D199V)A) delayed CXCR2 internalization similarly to CXCR1. Replacing Asp(199) with Asn (B(D199N)) restored CXCR2 rapid internalization. Structure modeling of the 2ECL of the receptors also suggested that Asp(199) plays a critical role in stabilizing and modulating CXCR2 rapid internalization relative to CXCR1. B(D199N) internalized rapidly but migrated as a single phosphorylated form like CXCR1 ( approximately 75 kDa), whereas B(2ECL)A and B(D199V)A showed slow and fast migrating forms like CXCR2 ( approximately 45 and approximately 65 kDa, respectively) but internalized like CXCR1. These data further undermine the role of receptor oligomerization in CXCL8 receptor internalization. Like CXCR1, B(D199V)A also induced sustained ERK activation and cross-desensitized Ca(2+) mobilization to CCR5 relative to B(D199N) and CXCR2. Altogether, the data suggest that the 2ECL of the CXCL8 receptors is important in modulating their distinct rate of down-regulation and thereby signal length and post-internalization activities.
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PMID:CXCR1 and CXCR2 activation and regulation. Role of aspartate 199 of the second extracellular loop of CXCR2 in CXCL8-mediated rapid receptor internalization. 1720 68

In the present study, we examined the role of Staphylococcus aureus protein A (SpA) in inducing inflammatory response in human corneal epithelial cells (HCECs). Exposure of HCECs to SpA induces rapid NF-kappaB activation and secretion of proinflammatory cytokine/chemokines (TNF-alpha and IL-8) in both concentration and time-dependent manner. Challenge of HCECs with live SpA(-/-) mutant S. aureus strains resulted in significantly reduced production of the cytokines when compared to the wild-type S. aureus strain. SpA also elicited the activation of MAP Kinases P38, ERK, but not JNK, in HCECs. SpA-induced production of proinflammatory cytokine were completely blocked by the NF-kappaB and p38 inhibitors and partially inhibited by the Jnk inhibitor. Pretreatment with anti-TLR2 neutralizing antibody had no effect on SpA-induced inflammatory response in HCECs, suggesting that this response is independent of TLR2 signaling. Moreover, unlike TLR2 ligands, SpA failed to induce the expression of antimicrobial peptides (hBD2 and LL-37) in HCECs. These studies indicate that SpA is a S. aureus virulence factor that stimulates HCEC inflammatory response through a pathway distinct from TLR2 in HCECs.
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PMID:Staphylococcus aureus protein A induced inflammatory response in human corneal epithelial cells. 1727 Jan 47

TNF-alpha induces some proinflammatory cytokines including IL-1beta, IL-6, IL-8, and itself by activation of NF-kappaB or MAPKs (p38, JNK, ERK). These cytokines play important roles in various inflammatory skin diseases, such as psoriasis. Recently it was also reported that expression of cyclin E is up-regulated by ERK pathway after TNF-alpha treatment. However, it was unknown whether curcumin, showing inhibitory effects on NF-kappaB and MAPKs, attenuates the expression of TNF-alpha-induced IL-1beta, IL-6, IL-8, and TNF-alpha as well as cyclin E expression in HaCaT cells. In this study, we investigated the inhibitory effect of curcumin on expression of proinflammatory cytokines and cyclin E in TNF-alpha-treated HaCaT cells. We found that curcumin inhibited the expression of TNF-alpha-induced IL-1beta, IL-6, and TNF-alpha, but not IL-8, in TNF-alpha-treated HaCaT cells as well as the TNF-alpha-induced cyclin E expression. In addition, curcumin inhibited the activation of MAPKs (JNK, p38 MAPK, and ERK) and NF-kappaB in TNF-alpha-treated HaCaT cells. Taken together, curcumin exerts anti-inflammatory and growth inhibitory effects in TNF-alpha-treated HaCaT cells through inhibition of NF-kappaB and MAPK pathways.
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PMID:Curcumin attenuates the expression of IL-1beta, IL-6, and TNF-alpha as well as cyclin E in TNF-alpha-treated HaCaT cells; NF-kappaB and MAPKs as potential upstream targets. 1727 96


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