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)

Epinastine is a potent antiallergic agent that has not only antihistaminic (H(1)) properties but also provides antileukotriene, anti-PAF and antibradykinin activities, which are associated with its antiallergic actions. Moreover, epinastine is very effective in inhibiting the release of chemical mediators from mast cells exposed to antigen. In addition, IL-8 release from eosinophils was inhibited by epinastine posttranscriptionally. Chemotatic movement of eosinophils was also blocked by epinastine. The increase in EEG power spectrum at low frequency region detected at frontal cortex is associated with drowsiness. No such change was induced by epinastine, while a marked increase was observed after ketotifen. In agreement with this, when the amount of H(1) blockers that penetrated through the BBB into the brain was estimated by means of PET, it was apparent that epinastine hardly penetrated the BBB. With regard to the current-voltage relationship of HERG currents, epinastine did not affect I(Kr), while a marked inhibition was seen after terfenadine or astemizole. These results indicated that epinastine does not suppress delayed rectifier potassium current of the heart and, consequently, no cardiotoxic action of epinastine was postulated. In man, epinastine is readily absorbed after oral administration and no significant change in pharmacokinetics was found during chronic administration. In teratological studies in rats, malformation and variation were not observed even at high doses of epinastine. In the clinical application of epinastine, it was shown that this drug is remarkably effective in the treatment of various dermatological diseases, such as chronic urticaria, psoriasis vulgaris and other pruritic dermatoses. Moreover, epinastine provides excellent clinical efficacy in the treatment of allergic rhinitis. Although efficacy of H(1) blockers in bronchial asthma is somewhat doubtful, the overall improvement rate in asthmatic patients was significantly higher in epinastine-treated patients (53.7%) compared to those treated with ketotifen (25%).
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PMID:Epinastine: An update of its pharmacology, metabolism, clinical efficacy and tolerability in the treatment of allergic diseases. 1284 34

TNF-alpha is a key cytokine in innate immune responses and is increased in psoriatic lesions. TNF-alpha has many effects, ranging from inflammation to apoptosis. These effects are reviewed to better understand the role of TNF-alpha as it relates to the pathogenesis and treatment of psoriasis. TNF-alpha increases production of pro-inflammatory molecules (e.g. IL-1, IL-6, IL-8, NF-kappa B, vasoactive intestinal peptide) and adhesion molecules (e.g. intercellular adhesion molecule-1, P-selectin, E-selectin). TNF-alpha promotes apoptosis through binding to the TNF-receptor 1; however, psoriatic lesions are hyperproliferative despite an increase in TNF-alpha. This paradox is partially explained as NF-kappa B activation seems to inhibit TNF-alpha-induced apoptosis. The importance of TNF-alpha and apoptosis in psoriasis is shown through the review of clinical trials using anti-TNF-alpha immunobiologics (e.g. etanercept, infliximab) and apoptosis-inducing treatments that result in clinical improvement of the disease.
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PMID:TNF-alpha and apoptosis: implications for the pathogenesis and treatment of psoriasis. 1285 85

Atopic dermatitis (AD) and psoriasis are the two most common chronic skin diseases. However patients with AD, but not psoriasis, suffer from frequent skin infections. To understand the molecular basis for this phenomenon, skin biopsies from AD and psoriasis patients were analyzed using GeneChip microarrays. The expression of innate immune response genes, human beta defensin (HBD)-2, IL-8, and inducible NO synthetase (iNOS) was found to be decreased in AD, as compared with psoriasis, skin (HBD-2, p = 0.00021; IL-8, p = 0.044; iNOS, p = 0.016). Decreased expression of the novel antimicrobial peptide, HBD-3, was demonstrated at the mRNA level by real-time PCR (p = 0.0002) and at the protein level by immunohistochemistry (p = 0.0005). By real-time PCR, our data confirmed that AD, as compared with psoriasis, is associated with elevated skin production of Th2 cytokines and low levels of proinflammatory cytokines such as TNF-alpha, IFN-gamma, and IL-1beta. Because HBD-2, IL-8, and iNOS are known to be inhibited by Th2 cytokines, we examined the effects of IL-4 and IL-13 on HBD-3 expression in keratinocyte culture in vitro. We found that IL-13 and IL-4 inhibited TNF-alpha- and IFN-gamma-induced HBD-3 production. These studies indicate that decreased expression of a constellation of antimicrobial genes occurs as the result of local up-regulation of Th2 cytokines and the lack of elevated amounts of TNF-alpha and IFN-gamma under inflammatory conditions in AD skin. These observations could explain the increased susceptibility of AD skin to microorganisms, and suggest a new fundamental rule that may explain the mechanism for frequent infection in other Th2 cytokine-mediated diseases.
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PMID:Cytokine milieu of atopic dermatitis, as compared to psoriasis, skin prevents induction of innate immune response genes. 1296 Mar 56

Psoriasis is a chronic inflammatory cutaneous disorder. Recent data indicate that T cells and cytokines are of major importance in the pathophysiology of this frequent immune disease. The cutaneous and systemic overexpression of several proinflammatory cytokines, particularly type-1 cytokines such as IL-2, IL-6, IL-8, IL-12, IFN-gamma and TNF-alpha, has been demonstrated. The overexpression of these proinflammatory cytokines is considered to be responsible for initiation, maintenance and recurrence of skin lesions. The cellular composition of the inflammatory infiltrate within the plaques as well as the keratinocyte hyperproliferation appears to be directed by cytokines as well. Thus, the overexpression of the chemoattractant IL-8 contributes to the accumulation of granulocytes, a characteristic finding in psoriatic lesions. In contrast to the overexpression of proinflammatory cytokines, a relatively low level of expression of the antiinflammatory cytokines IL-1RA and IL-10 has been found, suggesting an insufficient counterregulatory capacity in psoriasis which might have a genetic background. The new pathophysiologic understanding of psoriasis offers the opportunity for well-targeted therapeutic interventions which should be more effective and better tolerated than the approaches used thus far. In fact, the cytokine imbalance represents an interesting target. This is supported by the therapeutic effects of IL-10, a type-2 cytokine with major influence on immunoregulation, since it inhibits type-1/proinflammatory cytokine formation.
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PMID:The pathophysiological role of cytokines in psoriasis. 1297 18

Psoriasis is an inflammatory T cell-mediated disease characterized by epidermal hyperplasia and parakeratosis, resulting in lesional areas of thick and scaling skin. Elevated levels of proinflammatory cytokines, including TNF-alpha, are found in psoriatic lesions. TNF-alpha has many effects in producing an inflammatory response such as stimulating production of pro-inflammatory molecules (eg, IL-1, IL-6, IL-8, NF-kappaB) and adhesion molecules (eg, ICAM-1, P-selectin, E-selectin). As such, TNF-alpha is a target for immunotherapy in the treatment of psoriasis and psoriatic arthritis. The role of TNF-alpha in the pathogenesis of psoriasis is reviewed, along with clinical trials demonstrating the efficacy of new anti-TNF-alpha immunobiologics in the treatment of psoriasis and psoriatic arthritis.
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PMID:Changing paradigms in dermatology: tumor necrosis factor alpha (TNF-alpha) blockade in psoriasis and psoriatic arthritis. 1467 19

Most of the matrix metalloproteinases (MMP) are not expressed in normal intact skin but they are upregulated in inflamed or diseased skin. The recently cloned MMP-19 is one of the few MMP members that are also expressed in healthy epidermis. In this study, we found that MMP-19 is generally coexpressed with cytokeratin 14 that is confined to keratinocytes of the stratum basale. MMP-19 was also detected in hair follicles, sebaceous glands, and eccrine sweat glands. Its expression, however, changed in cutaneous diseases exhibiting increased alternations of epidermal proliferation, such as psoriasis, eczema, and tinea. In the affected area, MMP-19 was also found in suprabasal and spinous epidermal layers. We also studied the regulation of MMP-19 expression at the protein level, as well as by using a promoter assay. The constitutive expression of MMP-19 was upregulated with phorbol myristate acetate and downregulated with retinoic acid and dexamethasone. Tumor necrosis factor-alpha, interleukin (IL)-6, TGF-beta, IL-15, IL-8, and RANTES as well as the bacterial compounds lipopolysaccharide and lipoteichoic acid did not show any profound effect in HaCaT cells. In contrast, type IV and type I collagens upregulated MMP-19 significantly. The dysregulation of MMP-19 expression in epidermis suggests its possible involvement in the perpetuation of cutaneous infections and proliferative disorders such as psoriasis.
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PMID:Matrix metalloproteinase-19 expression in normal and diseased skin: dysregulation by epidermal proliferation. 1470 97

Type 1, or cellular, immune response is characterized by overproduction of TNF-alpha, IFN-gamma, IL-1, IL-2 and IL-8 and is the underlying immune mechanism of psoriasis, alopecia areata, rheumatoid arthritis, Crohn's disease, multiple sclerosis, insulin-dependent diabetes mellitus and experimental autoimmune uveitis (EAU). Type 2 immune response is seen in antibody-mediated autoimmune diseases. Based on the pharmacokinetic effects of cetirizine and allopurinol, this paper introduces these two safe and inexpensive drugs as novel potential agents against cell-mediated autoimmune disorders. Cetirizine, supposed to inhibit DNA binding activity of NF-kappa B, inhibits the expression of adhesion molecules on immunocytes and endothelial cells and the production of IL-8 and LTB4, two potent chemoattractants, by immune cells. It induces the release of PGE2, a suppressor of antigen presentation and MHC class II expression, from monocyte/macrophages and reduces the number of tryptase positive mast cells in inflammation sites. Tryptase is a chemoattractant, generates kinins from kininogen, activates mast cells, triggers maturation of dendritic cells and stimulates the release of IL-8 from endothelial cells and the production of Th1 lymphokines by mononuclear immunocytes. Allopurinol is a free radical scavenger, suppresses the production of TNF-alpha and downregulates the expression of ICAM-1 and P2X(7) receptors on monocyte/macrophages. ICAM-1 serves as a ligand for LFA-1 (on T lymphocytes), allowing proper antigen presentation. P2X(7) receptors are thought to be involved in IL-1beta release, mitogenic stimulation of T lymphocytes and the probable cytoplasmic communication between macrophages and lymphocytes at inflammation sites. Allopurinol was markedly more effective than prednisolone in treating experimental autoimmune uveitis and in combination with cyclosporine suppressed the inflammatory reaction of this condition more effectively than either agent alone. As allopurinol is a competitive inhibitor of xanthine oxidase and decreases serum levels of uric acid, which is protective against multiple sclerosis, it should preferably be coadministered with uric acid precursors in the treatment of this condition. Cetirizine and allopurinol may prove of benefit in the treatment of various cellular autoimmune disorders.
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PMID:Cetirizine and allopurinol as novel weapons against cellular autoimmune disorders. 1503 12

Human airway trypsin-like protease (HAT), a novel serine protease in the airways, enhances cell growth and IL-8 production. The expression and role of HAT in the skin however, is unknown. Immunofluorescence staining and reverse transcription (RT)-PCR were done to know HAT production in normal and psoriatic tissues and keratinocyte cell lines. Cell growth and/or IL-8 release analyses were made by bromo-deoxyuridine (BrdU) uptake and ELISA. Psoriatic epidermis showed more extensive immunofluorescence expression of HAT, and less extensive expression of protease-activated receptor (PAR)-2. RT-PCR demonstrated a higher HAT and a lesser PAR-2 mRNA expressions in psoriatic epidermis. Normal keratinocyte and epidermoid carcinoma cell lines expressed HAT and PAR-2 mRNA, and immortalized keratinocytes (HaCaT) expressed PAR-2, but not HAT mRNA. PAR-2 was detected along the keratinocyte surface in culture and became invisible upon HAT stimulation, suggesting a process of its internalization. HAT or PAR-2 activating peptide did not enhance BrdU uptake, but induced an IL-8 release. Treatment with HAT and IL-1beta synergistically increased the effect of IL-8 release. Inhibition of PAR-2 resulted in a decreased HAT-induced IL-8 release. Thus, HAT might promote PAR-2-mediated IL-8 production to accumulate inflammatory cells in the epidermal layer of psoriasis.
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PMID:Human airway trypsin-like protease induces PAR-2-mediated IL-8 release in psoriasis vulgaris. 1510 84

Tumour necrosis factor (TNF)-alpha is thought to play a major role in the pathophysiology of psoriasis. Good clinical responses of psoriasis to anti-TNF-alpha-based therapies have recently been demonstrated. We studied the effect of infliximab, a monoclonal antibody against TNF-alpha, on chemokine expression in pustular psoriasis. A 61-year-old man with a 2-year history of severe pustular psoriasis of von Zumbusch type who did not respond to conventional therapies responded rapidly to treatment with infliximab. The clinical response was reflected by an immediate and effective reduction of the neutrophil-attractant chemokines interleukin (IL)-8 and growth-related oncogene (Gro)-alpha as well as of monocyte chemoattractant protein (MCP)-1, as determined by mRNA in situ hybridization of lesional skin. No expression before or after treatment was seen for monokine induced by interferon (IFN)-gamma (MIG) and IFN-inducible protein (IP)-10. Thus, in pustular psoriasis the chemokine expression pattern is dominated by neutrophil-attractant chemokines and MCP-1 while, in contrast to plaque psoriasis, IFN-gamma-inducible lymphocyte-attractant chemokines such as IP-10 and MIG are not abundant. We conclude that anti-TNF-alpha treatment with infliximab is an effective therapy in severe pustular psoriasis which is reflected by downregulation of disease-promoting chemokines such as IL-8, Gro-alpha and MCP-1.
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PMID:Treatment of recalcitrant pustular psoriasis with infliximab: effective reduction of chemokine expression. 1514 18

Psoriasis is a chronic inflammatory skin disorder characterized by accumulation of Th1-type T cells and neutrophils, regenerative keratinocyte proliferation and differentiation, and enhanced epidermal production of antimicrobial peptides. The underlying cause is unknown, but there are some similarities with the immunologic defense program against bacteria. Development of psoriasiform skin lesions has been reported after administration of granulocyte colony-stimulating factor (G-CSF), a cytokine induced in monocytes by bacterial antigens. To further investigate the relation between this type of cytokine-induced dermatitis and psoriasis, we analyzed the cutaneous cytokine profile [tumor necrosis factor-alpha (TNF-alpha), interferon-gamma, transforming growth factor-beta1 (TGF-beta1), interleukin-10 (IL-10), IL-12p35 and p40, and IL-8] and expression of markers of epidermal activation [Ki-67, cytokeratin-16, major histocompatibility complex (MHC) class II, intercellular adhesion molecule-1 (ICAM-1)] in a patient who developed G-CSF-induced psoriasiform dermatitis by using quantitative real-time reverse transcriptase-polymerase chain reaction and immunohistology. The histologic picture resembled psoriasis with regard to epidermal hyperparakeratosis and the accumulation of lymphocytes in the upper corium. CD8(+) T cells were found to infiltrate the epidermis which was associated with an aberrant expression of Ki-67, cytokeratin-16, MHC class II, and ICAM-1 on adjacent keratinocytes. As compared to normal skin (n = 7), there was an increased expression of TNF-alpha, IL-12p40, and IL-8, a decreased expression of TGF-beta1, and a lack of IL-10, similar to the findings in active psoriasis (n = 8). Therefore, G-CSF may cause a lymphocytic dermatitis that, similar to psoriasis, is characterized by a pro-inflammatory Th1-type cytokine milieu and an epidermal phenotype indicative of aberrant maturation and acquisition of non-professional immune functions.
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PMID:Granulocyte colony-stimulating-factor-induced psoriasiform dermatitis resembles psoriasis with regard to abnormal cytokine expression and epidermal activation. 1518 19


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