Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P05231 (interleukin-6)
 23,907 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Interleukin-6, a multifunctional cytokine upon binding to its receptor on hepatocytes regulates production of acute phase proteins involved in local and systemic inflammation. Gene expression and biosynthesis of IL-6 and its receptor (IL-6 R/gp130) is under complex regulation. Histamine, in addition to its principal role in immediate type hypersensitivity has been described to modulate IL-6 production and expression of IL-6 receptor. In this study, the IL-6 and IL-6 receptor expression was examined in histamine deficient histidine decarboxylase (HDC) knock-out mouse model. Our data suggest that in histamine deficient mice the inducibility of IL-6 is significantly reduced, whilst more IL-6 receptor/gp130 mRNA expresses in the liver than in wild type (HDC(+/+)) mice. These in vivo findings confirm earlier in vitro results and emphasize the efficacy of antihistamines in local IL-6 related processes.
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PMID:Inverse regulation of interleukin-6 (IL-6) and IL-6 receptor in histamine deficient histidine decarboxylase-knock-out mice. 1180 46

Chlamydophila (Chlamydia) pneumoniae (C. pneumoniae) is the third most common cause of community-acquired pneumonia and is probably involved in the development of certain chronic inflammatory diseases, including atherosclerosis and adult-onset asthma. Histamine, synthesized by histidine decarboxylase (HDC) from L-histidine, plays an essential role in allergic and inflammatory processes and in cell differentiation. The effect of C. pneumoniae infection on the expression of HDC has not been examined. In the present study, normal Balb/c mice and HDC knockouts, and control mice with a CD1 background were infected intranasally with C. pneumoniae. On days 1, 3, 7, 16 and 31 after infection, the normal Balb/c mice were sacrificed and divided into three groups. In the homogenized lungs of the first group, C. pneumoniae titres were determined and demonstrated peak levels on day 7. HDC production was revealed by a Western blot assay throughout the observation period of 1-16 days, and cytokine concentrations were determined by ELISA. The interleukin-3 (IL-3) and interleukin-6 (IL-6) levels were highest on day 1 and on days 1-3, respectively; the interferon-gamma (IFN-gamma) and interleukin-4 (IL-4) levels reached the maximum on day 7, but the quantity of IL-4 was still three times higher than that in the control group 16 days after infection. The lungs of the mice in the second group were processed for the in situ demonstration of HDC activity, while the lungs in the third group were stained for C. pneumoniae antigen. The HDC activity was increased predominantly in the bronchial epithelial cells, while C. pneumoniae antigens were expressed especially in the interstitial macrophages. The HDC knockout mice exhibited a higher survival rate after C. pneumoniae infection than did the control mice. These results point to a strong association between local histamine production and other inflammatory mediators and are novel in demonstrating the role of histamine in the pathomechanism of C. pneumoniae infections.
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PMID:Chlamydophila (Chlamydia) pneumoniae induces histidine decarboxylase production in the mouse lung. 1455 83

Histamine is a major inflammatory molecule released from the mast cell, and is known to activate endothelial cells. However, its ability to modulate endothelial responses to bacterial products has not been evaluated. In this study we determined the ability of histamine to modulate inflammatory responses of endothelial cells to Gram-negative and Gram-positive bacterial cell wall components and assessed the role of Toll-like receptors (TLR) 2 and 4 in the co-operation between histamine and bacterial pathogens. Human umbilical vein endothelial cells (HUVEC) were incubated with lipopolysaccharide (LPS), lipoteichoic acid (LTA), or peptidoglycan (PGN) in the presence or absence of histamine, and the expression and release of interleukin-6 (IL-6), and NF-kappaB translocation were determined. The effect of histamine on the expression of mRNA and proteins for TLR2 and TLR4 was also evaluated. Incubation of HUVEC with LPS, LTA and PGN resulted in marked enhancement of IL-6 mRNA expression and IL-6 secretion. Histamine alone markedly enhanced IL-6 mRNA expression in HUVEC, but it did not stimulate proportional IL-6 release. When HUVEC were incubated with LPS, LTA, or PGN in the presence of histamine marked amplification of both IL-6 production and mRNA expression was noted. HUVEC constitutively expressed TLR2 and TLR4 mRNA and proteins, and these were further enhanced by histamine. The expression of mRNAs encoding MD-2 and MyD88, the accessory molecules associated with TLR signalling, were unchanged by histamine treatment. These results demonstrate that histamine up-regulates the expression of TLR2 and TLR4 and amplifies endothelial cell inflammatory responses to Gram-negative and Gram-positive bacterial components.
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PMID:Histamine induces Toll-like receptor 2 and 4 expression in endothelial cells and enhances sensitivity to Gram-positive and Gram-negative bacterial cell wall components. 1537 83

Histamine is a potent stimulator of nerve growth factor (NGF) production in the central nerve system and in the periphery as well. In this review, the biochemical mechanisms of histamine-stimulated NGF synthesis and secretion, and interactions between histamine, interleukin-1beta, and interleukin-6 are discussed. The main signalling pathway, involved in the stimulation of NGF production by histamine, includes activation of histamine H(1)-receptor, stimulation of Ca(2+)-dependent protein kinase C and mitogen-activated protein kinase. The same signalling pathway is involved in the interactions between histamine, interleukin-1beta, and interleukin-6, where NGF secretion is amplified. Whereas histamine and interleukin-1beta cause additive stimulatory effect on NGF secretion, interaction between histamine and interleukin-6 causes a long-term synergism. Thus, activation of histamine H(1)-receptor-protein kinase C-mitogen-activated protein kinase signalling pathway plays a crucial role not only in the direct stimulation of NGF secretion by histamine, but also in the indirect stimulation via different types of interactions between histamine, interleukin-1beta, and interleukin-6, which may have important therapeutic implications in modulation of NGF production.
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PMID:Multiple role of histamine H1-receptor-PKC-MAPK signalling pathway in histamine-stimulated nerve growth factor synthesis and secretion. 1688 95

Moringaceae, which belongs to the Moringa oleifera Lam. family, is a well-known herb used in Asian medicine as an antiallergic drug. In the present study, the efficacy of the n-butanol extract of the seeds of the plant (MONB) is examined against ovalbumin-induced airway inflammation in guinea pigs. The test drugs (MONB or dexamethasone) are administered orally prior to challenge with aerosolized 0.5% ovalbumin. During the experimental period, bronchoconstriction tests are performed, and lung function parameters are measured. The blood and bronchoalveolar lavage fluid are collected to assess cellular content, and serum is used for cytokine (tumor necrosis factor-alpha, interleukin-4, and interleukin-6) assays. Histamine assays of lung tissue are performed using lung tissue homogenate. The results suggest that in ovalbumin-sensitized model control animals, tidal volume is decreased, respiration rate is increased, and both the total and differential cell counts in blood and bronchoalveolar lavage fluid are increased significantly compared with nonsensitized controls. MONB treatment shows improvement in all parameters except bronchoalveolar lavage tumor necrosis factor-alpha and interleukin-4. Moreover, MONB treatment demonstrates protection against acetylcholine-induced bronchoconstriction and airway inflammation. These results indicate that MONB has an inhibitory effect on airway inflammation. Thus, MONB possesses an antiasthmatic property through modulation of the relationship between Th1/Th2 cytokine imbalances.
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PMID:Inhibitory effect of n-butanol fraction of Moringa oleifera Lam. seeds on ovalbumin-induced airway inflammation in a guinea pig model of asthma. 1996 43

Summary Histamine is a well-recognized modulator of vascular inflammation. We have shown that histamine, acting via H1 receptors (H1R), synergizes lipopolysaccharide (LPS)-induced production of prostaglandin I(2) (PGI(2)), PGE(2) and interleukin-6 (IL-6) by endothelial cells. The synergy between histamine and LPS was partly attributed to histamine -induced expression of Toll-like receptor 4 (TLR4). In this study, we examined whether LPS stimulates the H1R expression in human coronary artery endothelial cells (HCAEC) with resultant enhancement of histamine responsiveness. Incubation of HCAEC with LPS (10-1000 ng/ml) resulted in two-fold to fourfold increases in H1R mRNA expression in a time-dependent and concentration-dependent fashion. In contrast, LPS treatment did not affect H2R mRNA expression. The LPS-induced H1R mRNA expression peaked by 4 hr after LPS treatment and remained elevated above the basal level for 20-24 hr. Flow cytometric and Western blot analyses revealed increased expression of H1R protein in LPS-treated cells. The specific binding of [(3)H]pyrilamine to H1R in membrane proteins from LPS-treated HCAEC was threefold higher than the untreated cells. The LPS-induced H1R expression was mediated through TLR4 as gene silencing by TLR4-siRNA and treatment with a TLR4 antagonist inhibited the LPS effect. When HCAEC were pre-treated with LPS for 24 hr, washed and challenged with histamine, 17-, 10- and 15-fold increases in PGI(2), PGE(2) and IL-6 production, respectively, were noted. Histamine-induced enhancement of the synthesis of PGI(2), PGE(2) and IL-6 by LPS-primed HCAEC was completely blocked by an H1R antagonist. The results demonstrate that LPS, through TLR4 activation, up-regulates the expression and function of H1R and amplifies histamine-induced inflammatory responses in HCAEC.
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PMID:Lipopolysaccharide induces H1 receptor expression and enhances histamine responsiveness in human coronary artery endothelial cells. 2125 12

Histamine is a potent mediator of inflammation and a regulator of innate and adaptive immune responses. However, the influence of histamine on microglia, the resident immune cells in the brain, remains uninvestigated. In the present study, we found that microglia can constitutively express all four histamine receptors (H1R, H2R, H3R, and H4R), and the expression of H1R and H4R can be selectively upregulated in primary cultured microglia in a dose-dependent manner by histamine. Histamine can also dose-dependently stimulate microglia activation and subsequently production of proinflammatory factors tumor necrosis factor (TNF)-alpha and interleukin-6 (IL-6). The antagonists of H1R and H4R but not H2R and H3R reduced histamine-induced TNF-alpha and IL-6 production, MAPK and PI3K/AKT pathway activation, and mitochondrial membrane potential loss in microglia, suggesting that the actions of histamine are via H1R and H4R. On the other hand, inhibitors of JNK, p38, or PI3K suppressed histamine-induced TNF-alpha and IL-6 release from microglia. Histamine also activated NF-kappa B and ammonium pyrrolidinedithiocarbamate, an inhibitor of NF-kappa B, and reduced histamine-induced TNF-alpha and IL-6 release. In summary, the present study identifies the expression of histamine receptors on microglia. We also demonstrate that histamine induced TNF-alpha and IL-6 release from activated microglia via H1R and H4R-MAPK and PI3K/AKT-NF-kappa B signaling pathway, which will deepen the understanding of microglia-mediated neuroinflammatory symptoms of chronic neurodegenerative disease.
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PMID:Histamine induces upregulated expression of histamine receptors and increases release of inflammatory mediators from microglia. 2475 87

Inflammatory bowel diseases (IBD) are a growing health problem worldwide, severely affecting patients' life qualities and life expectancies. Therapeutic options, which are rare and focus on symptoms associated with the disease, suffer from increasing numbers of patients refractory to the established strategies. Thus, in order to generate new therapeutic regimens, the detailed understanding of the pathogenic mechanisms causing IBD is necessary. Histamine is an inflammatory mediator associated with IBD. Four histamine receptors are currently known of which the histamine H4-receptor (H4R) has been shown to possess a pro-inflammatory function in several experimental models of inflammatory diseases, including dextran sodium sulfate (DSS)-induced colitis in mice. No single model reflects the complexity of human IBD, but each model provides valuable information on specific aspects of IBD pathogenesis. While DSS-induced colitis mostly relies on innate immune mechanisms, trinitrobenzene sulfonic acid (TNBS)-induced colitis rather reflects T-cell mechanisms. Consequently, an observation made in a single model has to be verified in at least one other model. Therefore, in the present study we investigated the effect of genetic blockade of H4R-signaling in mice subjected to the model of TNBS-induced acute colitis. We analyzed severity and progression of clinical signs of colitis, as well as histopathologic alterations in the colon and local cytokine production. Genetic ablation of H4R expression worsened clinical signs of acute colitis and histological appearance of colon inflammation after TNBS application. Moreover, TNBS instillation enhanced local synthesis of inflammatory mediators associated with a neutrophilic response, i.e., CXCL1, CXCL2, and interleukin-6. Lastly, also myeloperoxidase concentration, indicative for the presence of neutrophils, was elevated in cola of TNBS-treated mice due to the absence of H4R expression. Our results indicate an anti-inflammatory role of histamine via H4R in TNBS-induced acute neutrophilic colitis in mice, thus questioning the strategy of pharmacological H4R blocked as new therapeutic option for patients suffering from IBD.
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PMID:Lack of Histamine H4-Receptor Expression Aggravates TNBS-Induced Acute Colitis Symptoms in Mice. 2895 41

As type-I-allergies show an increasing prevalence in the general populace, orthodontic patients may also be affected by histamine release during treatment. Human periodontal ligament fibroblasts (PDLF) are regulators of orthodontic tooth movement. However, the impact of histamine on PDLF in this regard is unknown. Therefore PDLF were incubated without or with an orthodontic compressive force of 2g/cm2 with and without additional histamine. To assess the role of histamine-1-receptor (H1R) H1R-antagonist cetirizine was used. Expression of histamine receptors and important mediators of orthodontic tooth movement were investigated. PDLF expressed histamine receptors H1R, H2R and H4R, but not H3R. Histamine increased the expression of H1R, H2R and H4R as well as of interleukin-6, cyclooxygenase-2, and prostaglandin-E2 secretion even without pressure application and induced receptor activator of NF-kB ligand (RANKL) protein expression with unchanged osteoprotegerin secretion. These effects were not observed in presence of H1R antagonist cetirizine. By expressing histamine receptors, PDLF seem to be able to respond to fluctuating histamine levels in the periodontal tissue. Increased histamine concentration was associated with enhanced expression of proinflammatory mediators and RANKL, suggesting an inductive effect of histamine on PDLF-mediated osteoclastogenesis and orthodontic tooth movement. Since cetirizine inhibited these effects, they seem to be mainly mediated via histamine receptor H1R.
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PMID:Effects of histamine on human periodontal ligament fibroblasts under simulated orthodontic pressure. 3276 23


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