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

We recently reported on the successful generation of immortalized (CEPI-17-CL4) cells from primary human corneal epithelial (P-CEPI) cells which exhibited phenotypic, immunohistochemical and metabolic characteristics akin to the P-CEPI cells. The aims of the present studies were to investigate the ligand binding and functional coupling of the histamine receptors to various biochemical and physiological systems in the P-CEPI and CEPI-17-CL4 cells and to relate these findings to the normal and/or pathophysiological role of histamine on the human ocular surface. Specific [3H]-pyrilamine binding to CEPI-17-CL4 cell homogenates comprised >93% of the total binding and represented interaction with an apparent single population of high affinity (Kd=3.76+/-0.78 nM; n=4) and saturable (Bmax = 1582+/-161 fmol g(-1) tissue) number of histamine-1 (H1) receptor binding sites on CEPI-17-CL4 cell homogenates. The H1-receptor selective antagonists, pyrilamine (Ki=3.6+/-0.84 nM, n=4) and triprolidine (Ki = 7.7+/-2.6 nM, n=3), potently displaced [3H]-pyrilamine binding, while the H2- and H3-receptor selective antagonists, ranitidine and clobenpropit, were weak inhibitors (K(i)s>13 microM). Histamine induced phosphoinositide (PI) hydrolysis 2.7-4.4 fold above basal levels and with a potency of 14.9+/-4.9 microM (n=9) and 4.7+/-0.2 microM (n=9) in P-CEPI and CEPI-17-CL4 cells, respectively. Histamine-induced PI turnover was antagonized by H1-receptor selective antagonist, triprolidine, with a potency (Ki) of 3.2+/-0.66 nM (n=10) and 3.03+/-0.8 nM (n=4) in P-CEPI and CEPI-17-CL4 cells, respectively, but weakly effected by 10 microM cimetidine and clobenpropit, H2- and H3-receptor antagonists. The PI turnover response was attenuated by pre-treatment of the cells with the selective phospholipase C inhibitor, U73122 (1-(6-((17beta-3-methoxyestra- 1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione) (IC50=4.8+/-2.4 microM, n = 3). Histamine stimulated intracellular Ca2+ ([Ca2+]i) mobilization in CEPI-17-CL4 cells with a potency of 6.3+/-1.5 microM (n=4). The histamine-induced [Ca2+]i mobilization was reduced by about 28% following pre-incubation of the cells with 4 mM EGTA. While triprolidine completely inhibited histamine-induced [Ca2+]i mobilization, it did not influence the bradykinin-induced [Ca2+]i mobilization response. Histamine (EC50s = 1.28-2.77 microM, n=3-4) concentration-dependently stimulated the release of interleukin-6 (IL-6), IL-8 and granulocyte macrophage colony-stimulating factor, but it did not significantly alter release of tumour necrosis factor-alpha, PGE2 or collagenase-1 (matrix metalloproteinase-1; MMP-1) from CEPI cells. However, IL-1 (10 ng ml(-1)), foetal bovine serum (10%) and phorbol-12-myristate-13-acetate (3 microg ml(-1)) were effective positive control secretagogues of all the cytokines, PGE2 and MMP-1, respectively, from these cells. It is concluded that the CEPI cells express H1-histamine receptors which are positively coupled to PI turnover and [Ca2+]i mobilization which may be directly or indirectly responsible for the release of various cytokines from these cells at physiologically and/or pathologically relevant concentrations.
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PMID:Pharmacology of [3H]-pyrilamine binding and of the histamine-induced inositol phosphates generation, intracellular Ca2+ -mobilization and cytokine release from human corneal epithelial cells. 986 65

Since its discovery in 1911, histamine has been recognized as a major mediator in allergic reactions and diseases, and today antihistamines remain important agents in the treatment of these conditions. In addition to its known effects on glands, vessels and sensory nerves, recent data have provided further evidence of histamine's proinflammatory actions, which appear to be mediated mainly by H1 receptors. Thus, findings indicate that histamine is a crucial mediator in both the early and late-phase reactions of an allergic response, playing important roles in cytokine release and in the adhesion process. Histamine has been shown to increase the adhesion of leucocytes to the endothelium and to stimulate production of IL-6 and IL-8 by endothelial cells. It also increases TNF alpha-induced IL-6 production and expression of adhesion molecules. These effects can be inhibited by H1 receptor antagonists. First-generation antihistamines, though moderately effective, showed poor selectivity and caused sedation, due to their penetration of the blood-brain barrier, and other troublesome side-effects. Second-generation antihistamines such as ebastine have increased potency due to greater selectivity for histamine receptors, and improved tolerability due to lack of penetration of the blood brain barrier. Recent studies have shown ebastine 10 mg daily to be effective, safe and well tolerated in the treatment of seasonal allergic rhinitis (SAR), with a rapid onset of action, symptom relief comparable to that seen with topical azelastine or oral loratadine 10 mg o.d., cetirizine 10 mg o.d. or terfenadine 60 mg b.i.d., and no significant side-effects. Ebastine therefore offers a new option in the treatment of seasonal allergic rhinitis.
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PMID:Histamine--a major role in allergy? 998 29

The allergic process is believed to consist of two phases: early and late. The early phase reaction is mainly induced by histamine released from mast cells. Histamine binding specific cell receptors produces clinical allergic symptoms. This mediator also activates neutrophils and eosinophils as well as being a chemoattractant for these cells. Histamine increases IL-8 level and evokes leukocyte rolling on endothelial cells. Thus histamine participates in both early and late-phase allergic responses.
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PMID:[Histamine as a mediator of allergic inflammation]. 1043 88

Mast cells and immature dendritic cells (DC) are in close contact in peripheral tissues. Upon activation, mast cells release histamine, a mediator involved in the immediate hypersensitivity reaction. We therefore tested whether histamine could affect human DC activation and maturation. Histamine induces CD86 expression on immature DC in a dose-dependent (significant at 10(-7) M) and transient manner (maximal after 24-h stimulation). Histamine also transiently up-regulates the expression of the costimulatory and accessory molecules, CD40, CD49d, CD54, CD80, and MHC class II. As a consequence, immature DC exposed for 24 h to histamine stimulate memory T cells more efficiently than untreated DC. In addition, histamine induces a potent production of IL-6, IL-8, monocyte chemoattractant protein 1, and macrophage-inflammatory protein 1alpha by immature DC and also up-regulates IL-1beta, RANTES, and macrophage-inflammatory protein 1beta but not TNF-alpha and IL-12 mRNA expression. Histamine activates immature DC through both the H1 and H2 receptors. However, histamine-treated DC do not have a phenotype of fully mature cells, as they do neither show significant changes in the expression of the chemokine receptors, CCR5, CCR7 and CXC chemokine receptor 4, nor expression of CD83 de novo. These data demonstrate that histamine activates immature DC and induces chemokine production, thereby suggesting that histamine, via stimulation of resident DC, may participate locally in T cell stimulation and in the late inflammatory reaction associated with allergic disorders.
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PMID:Histamine induces CD86 expression and chemokine production by human immature dendritic cells. 1134 15

The Plasmodium falciparum translationally controlled tumor protein (TCTP) is a homolog of the mammalian histamine-releasing factor (HRF), which causes histamine release from human basophils and IL-8 secretion from eosinophils. Histamine, IL-8, and eosinophils have been reported to be elevated in patients with malaria. This study was undertaken to determine whether malarial TCTP is found in the plasma of malaria-infected patients and to determine whether it has HRF biologic activity. Malarial TCTP was found in lightly infected human volunteers and in heavily infected Malawian children, but not in uninfected patients. Recombinant malarial TCTP, like HRF, stimulated histamine release from basophils and IL-8 secretion from eosinophils in vitro. Whereas malarial TCTP was less active than HRF, the concentrations that were effective in vitro could be achievable in vivo. These data suggest that malarial TCTP, present in human plasma during a malarial illness, may affect host immune responses in vivo.
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PMID:Immune mimicry in malaria: Plasmodium falciparum secretes a functional histamine-releasing factor homolog in vitro and in vivo. 1153 39

It is known that large amounts of histamine are stored in mast cells located in the superficial dermis of the skin and can be released upon appropriate stimulation. However, the effects of histamine on keratinocyte function have not been well characterized. We therefore examined the capacity of histamine to modulate the production of interleukin (IL)-6 and IL-8 by keratinocytes. We found that histamine significantly augmented the production of IL-6 and IL-8 in a dose- and time-dependent manner. The enhancing effects of histamine were completely inhibited by a potent H1 receptor (H1R) antagonist, emedastine difumarate. Pyrilamine (a much weaker H1R antagonist) and cimetidine (an H2R antagonist) only partially inhibited the enhancing effects of histamine. The histamine-induced up-regulation of IL-6 and IL-8 production, however, was completely abrogated by a combination of pyrilamine and cimetidine. The IL-6 production was significantly enhanced by interferon (IFN)-gamma. Interestingly, IFN-gamma and IL-4 both significantly augmented the histamine-induced IL-6 production. On the other hand, the production of IL-8 was inhibited by IFN-gamma, and IFN-gamma and IL-4 both completely abrogated the histamine-induced IL-8 production. These results suggest that the histamine-induced IL-6 production and IL-8 production are differentially regulated by IFN-gamma and IL-4. Histamine may be an important modulator of cytokine production in epidermal milieu.
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PMID:Histamine-induced IL-6 and IL-8 production are differentially modulated by IFN-gamma and IL-4 in human keratinocytes. 1191 28

IgE plays a key role in allergic asthma. We investigated whether omalizumab treatment of patients with moderate to severe allergic asthma leads to changes in inflammatory mediators and clinical symptoms. This sub-study was conducted on 35 patients with a positive skin prick test (SPT) requiring daily administration of beclomethasone dipropionate (500-1,000 microg), who participated in a multicentre, randomised, double-blind, placebo-controlled study. Omalizumab or placebo was administered at 0.016 mg/kg/IgE every 4 weeks. Patients recorded peak expiratory flow, asthma symptom score and beta(2)-agonist use in daily diaries and spirometry was performed at each visit. beta(2)-Agonist use and SPT wheal reaction decreased significantly (p < 0.05). Circulating levels of IL-5, IL-6, IL-8, IL-10, IL-13 and s-ICAM were measured before and after 16 weeks of treatment. IL-13 and s-ICAM were measured before and after 16 weeks of treatment. IL-13 decreased significantly (p < 0.01). IL-5 and IL-8 decreased in the omalizumab group compared to baseline. The other circulating mediators did not demonstrate any changes. Histamine release was significantly reduced (p < 0.01). Airway resistance (p < 0.05) and the provocative concentration inducing a 20% decrease in FEV(1) (p < 0.05) were measured before, after 16 weeks, and 3 months after completion of treatment. Both parameters decreased significantly (p < 0.05). Peripheral eosinophil count decreased significantly compared to placebo (p < 0.01). These findings suggest that omalizumab has potential as a novel treatment for allergic asthma.
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PMID:Immunological and clinical changes in allergic asthmatics following treatment with omalizumab. 1275 89

Conjunctival epithelial cells do not act only as mechanical barriers, preventing the entry of particles, bacteria, viruses, and noxious substances into the eye but they are also active participants in the regulation of allergic inflammation via expressing adhesion/effector molecules (intercellular adhesion molecule-1, vascular cell adhesion molecule-1, human leukocyte antigen-DR, CD40/CD40L, Fas/Fas ligand) on their surfaces and releasing numerous proinflammatory cytokines, such as eotaxin, regulated on activation normal T-cell expressed and released (RANTES), macrophage inflammatory protein-1, interleukin (IL)-8, IL-6, and tumor necrosis factor-a, which are necessary for the proliferation, differentiation, activation, and chemotaxis of various inflammatory cells into the conjunctiva. Histamine, released from the conjunctival mast cells, might stimulate the synthesis of proinflammatory molecules such as IL-6 and IL-8 by the epithelial cells through the receptors that couple to inositol phosphate generation and, therefore, amplify the allergic response. The relationship between the epithelium and allergy should be considered in detail in future studies aiming at an effective control and treatment of all forms of allergic conjunctivitis.
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PMID:Epithelial cells in ocular allergy. 1279 Dec 15

Histamine H1 receptor (H1R), a therapeutic target for alleviation of acute allergic reaction, may be also involved in mediating inflammatory responses via effects on cytokine production. However, the mechanisms whereby histamine induces cytokine production are poorly defined. In this study, we comprehensively investigated the signaling pathway involved in cytokine expression caused by histamine, using native human epidermal keratinocytes. We confirmed the expression of functional H1R by reverse transcription-polymerase chain reaction (RT-PCR), Western blotting and histamine-induced Ca(2+) elevation. Histamine induced concentration- and time-dependent production of granulocyte-macrophage-colony stimulating factor (GM-CSF), interleukin (IL)-8 and IL-6, which was completely blocked by olopatadine, an H1 antagonist. Histamine activated the phosphorylation of protein kinase C (PKC), c-Raf, mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK), extracellular signal-regulated kinase (ERK), I kappa B kinase (IKK), inhibitory kappa B (I kappa B)-alpha and nuclear factor-KB (NF-kappa B) p65, which was inhibited by Ro-31-8220, a PKC inhibitor. Also, Ro-31-8220 significantly suppressed the expression of these cytokines. BAPTA-AM, an intracellular Ca(2+) chelator, also reduced PKC phosphorylation and cytokine expression. PD98059, a MEK inhibitor, and BAY 11-8702, an I kappa B-alpha inhibitor, reduced ERK and NF-kappa B cascade activation, respectively, with little effect on PKC phosphorylation. PD98059 preferentially inhibited GM-CSF production whereas BAY 11-8702 prevented IL-8 and IL-6 production. Furthermore, in addition to the above cytokines, histamine stimulated the biosynthesis and/or release of numerous keratinocyte-derived mediators, which are probably regulated by the ERK or NF-kappa B cascades. Our study suggests that histamine activates Ca(2+)-dependent PKC isoforms that play crucial roles in the activation of Raf/MEK/ERK and IKK/I kappa B/NF-kappa B cascades, leading to up-regulation of cytokine expression. Thus, the anti-inflammatory benefit of H1 antagonists may be in part due to prevention of cytokine production.
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PMID:Histamine H1 receptor antagonist blocks histamine-induced proinflammatory cytokine production through inhibition of Ca2+-dependent protein kinase C, Raf/MEK/ERK and IKK/I kappa B/NF-kappa B signal cascades. 1565 35

The mechanism of chronic mast cell activation in asthma is unclear. Monomeric immunoglobulin (Ig)E in the absence of allergen induces mediator release from rodent mast cells, indicating a possible role for IgE in the continued activation of mast cells within the asthmatic bronchial mucosa. In this study it was investigated whether monomeric IgE induces Ca2+ influx and mediator release from human lung mast cells (HLMC). Purified HLMC were cultured for 4 weeks and then exposed to monomeric human myeloma IgE. Ratiometric Ca2+ imaging was performed on single fura-2-loaded cells. Histamine release was measured by radioenzymatic assay; leukotriene C4 (LTC4) and interleukin (IL)-8 were measured by ELISA. At concentrations experienced in vivo, monomeric IgE induced dose-dependent histamine release, LTC4 production and IL-8 synthesis. This was associated with a rise in cytosolic free Ca2+. Enhanced histamine release was still evident 1 week after initial exposure to IgE suggesting that continued exposure maintains enhanced secretion. Monomeric immunoglobulin E alone activates cultured human lung mast cells initiating Ca2+ influx, degranulation, arachidonic acid metabolism and cytokine synthesis. These findings support the hypothesis that immunoglobulin E loading of mast cells within the asthmatic airway contributes to the disordered airway physiology of this disease.
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PMID:Activation of human lung mast cells by monomeric immunoglobulin E. 1620 8


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