UNIPROT:P10145 - FACTA Search

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)

A proinflammatory cytokine cascade, including IL-1 alpha, IL-1 beta, TNF-alpha, IL-6, and IL-8, is activated in response to infection or immunologic insult. Besides their immunologic effects, several of these mediators stimulate bone resorption and inhibit bone formation. Osteocalcin, the most abundant noncollagenous protein present in bone, is an osteoblast-specific product whose production closely correlates with bone formation, and which has also been implicated in control of bone resorption. IL-1 and TNF have previously been shown to down-regulate osteocalcin production in vitro and in vivo, although the mechanism of this inhibition is unknown. In the present studies, IL-1 beta and TNF-alpha both inhibited 1,25-dihydroxyvitamin D3-stimulated production of osteocalcin protein and mRNA by ROS 17/2.8 osteosarcoma cells, whereas IL-6 had no effect on protein and only weakly inhibited mRNA. To determine if down-regulation was exerted at the transcriptional level, an osteocalcin promoter-chloramphenicol acetyltransferase (CAT) fusion gene was constructed (PHOC-CAT). After transient transfection of PHOC-CAT into ROS 17/2.8 osteosarcoma cells, reporter CAT activity was up-regulated by vitamin D at concentrations above 10(-12) M. In screening studies, TNF-alpha (-57%) and IL-6 (-37%) inhibited vitamin D-stimulated osteocalcin transcription, whereas IL-1 alpha, IL-1 beta, and IL-8 had no effect. Other immune cytokines and growth factors, including IL-2, IL-3, IL-7, and M-CSF, also failed to regulate osteocalcin transcription. Despite their lack of promoter regulation, IL-1 alpha and IL-1 beta also stimulated PGE2 production by ROS 17/2.8, further confirming the ability of the host cell to respond to these mediators. In dose-response experiments, down-regulation by TNF-alpha was significant at concentrations as low as 0.14 pM (0.1 U/ml), whereas approximately 10(4)-fold higher concentration of IL-6 was required to exert a similar effect. TNF-alpha-mediated down-regulation was unaffected by indomethacin. These data demonstrate that of these cytokines, TNF-alpha alone potently down-regulates osteocalcin promoter function, whereas IL-1 acts post-transcriptionally, possibly by reducing mRNA stability. Heterogeneity therefore exists among the proinflammatory cytokines with respect to the level at which control of osteocalcin expression is exerted.
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PMID:Proinflammatory cytokines tumor necrosis factor-alpha and IL-6, but not IL-1, down-regulate the osteocalcin gene promoter. 130 41

Sodium Fluoride (NaF) is the only medication so far clinically available with a bone formation stimulating property, through its peculiar mitogenic dose-dependent action on the osteoblast cell line. Bone strength is commensurate to bone mass, and in a condition with fragility fractures, like osteoporosis, it seems logical to restore bone mass without weakening bone strength. However, as with any active drug. NaF therapy requires adhesion to elementary rules if drawbacks are to be prevented. A first mandatory rule is not to prescribe NaF without calcium supplementation, if bone loss at the appendicular skeleton is to be avoided; to prevent this, the availability of monofluorophosphate (MFP), containing the fluoride and calcium salts in the same preparation has enhanced the compliance to calcium supplementation. A second rule is not to give supraphysiological doses of vitamin D, for the same reason. Third, if one wants to avoid a calcium shift from cortical to trabecular bone and osteomalacia, one should use small doses of NaF, of the order of 50 mg/day. With this in mind, the bioavailability of the drug has to be taken into account, particularly its gastrointestinal absorption which is dramatically enhanced if a plain non entericoated (EC) capsule is used, as compared to that of an EC tablet with the same face value. Too much NaF is deleterious to bone, a fact known for years. Already in 1972, it was noted that in all patients receiving 60 mg or more of NEC NaF, daily, morphologically abnormal bone developed and which appeared irregular and contained areas of incompletely mineralized bone. The bone was histologically and microradiographically normal in patients receiving 45 mg or less of NEC NaF/day. Fourth, NaF therapy is contraindicated in renal insufficiency owing to an enhanced retention in the skeleton. NaF is, however, by no means the ideal medication, because its therapeutic window is narrow. It has many bothersome drawbacks, and notably it is irritating for the gastric mucosa, a hazard which may be partly circumvented by the use of an Ec or slow release tablet. Furthermore, peripheral stress fractures may occur, and, in our experience, they were seen in 17% of patients, almost exclusively in females with a low lumbar BMD. Their occurrence should be curtailed by not allowing an increase in alkaline phosphatase activity of more than 50%. This is a relatively benign complication, because no stress fracture degenerated into a complete fracture. In all cases, the stress fractures healed after a transitory drug discontinuation. If there is some concern about cortical bone, NaF therapy may be associated with an antiresorber like estrogens which will prevent any further bone loss, and does not impair the response to NaF. NaF therapy should be reserved for patients suffering chiefly from trabecular osteoporosis and should be avoided in senile osteoporosis, because of a frequently impaired renal function. Currently, we would recommend in clinical practice a daily dose of 50 mg EC-NaF or 150 mg Ca-MFP as the therapy of involutional osteoporosis in women, reserving the dose of 75 mg EC-NAF or 200 mg MFP for males or female patients resistant to lower dose. The therapy should be maintained for 2 to 3 years, or more, according to the bone response, taking into account that patients with the vertebral crush fracture syndrome have lost on average 30%, as compard to the young adult mean.
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PMID:Fluoride therapy of type I osteoporosis. 884 58

Psoriasis is a common hyperproliferative and inflammatory skin disease with a prevalence of 0.5-3%. Lesional skin is characterized by pathological overexpression of proinflammatory cytokines such as IL-8 and its receptor and the decreased presence of negative regulatory control factors like the anti-oncogene p53. The expression of these genes can be modulated in the opposite direction by antipsoriatic drugs. Another possible candidate gene is the receptor for the anti-inflammatory cytokine IL-10 (IL-10R). Recently, vitamin D3 and its analogues have attracted interest as new therapeutic agents in the treatment of psoriasis. In extension of these findings we studied here the effect of the physiologically active metabolite, 1,25-dihydroxyvitamin D3 (calcitriol) and its synthetic analogue calcipotriol (MC 903) on the expression of the IL-10R in HaCaT cells by RT-PCR. IL-10 receptor gene expression was effectively induced in the range of 10(-8)-10(-9) M. Upregulation by calcitriol was about 10-fold, by calcipotriol 12-fold. Induction of the receptor for the anti-inflammatory cytokine IL-10 may be involved in the antipsoriatic action of vitamin D derivatives.
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PMID:1,25-(OH)2-vitamin D3 and calcipotriol induce IL-10 receptor gene expression in human epidermal cells. 911 16

1Alpha,25-dihydroxyvitamin D3 (1,25-(OH)2-D3), the active metabolite of vitamin D, can inhibit NF-kappaB activity in human MRC-5 fibroblasts, targeting DNA binding of NF-kappaB but not translocation of its subunits p50 and p65. The partial inhibition of NF-kappaB DNA binding by 1,25-(OH)2-D3 is dependent on de novo protein synthesis, suggesting that 1,25-(OH)2-D3 may regulate expression of cellular factors which contribute to reduced DNA binding of NF-kappaB. Although NF-kappaB binding is decreased by 1,25-(OH)2-D3 in MRC-5 cells, IL-8 and IL-6 mRNA levels are only moderately downregulated, demonstrating that inhibition of NF-kappaB DNA binding alone is not sufficient for optimal downregulation of these genes.
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PMID:1Alpha,25-dihydroxyvitamin D3 decreases DNA binding of nuclear factor-kappaB in human fibroblasts. 980 Nov 42

Kaposi sarcoma (KS) is responsive to a number of different steroid hormones, such as glucocorticoids and retinoids. An active metabolite of vitamin D, 1alpha,25 dihydroxyvitamin D(3), was used to study the effect of this steroid hormone in KS. Steroid hormones exert their effect through their cognate nuclear receptors, which for vitamin D metabolites is the vitamin D receptor (VDR). It was first shown that KS cell lines and primary tumor tissue express high levels of VDR, whereas endothelial cells had minimal expression and fibroblasts had no expression. Second, KS cell growth was inhibited by VDR agonist 1alpha,25 dihydroxyvitamin D(3) with a 50% inhibitory concentration of 5 x 10 -8 mol/L, whereas endothelial cells and fibroblast cells showed no response. Studies on the mechanism of KS tumor growth inhibition by 1alpha,25 dihydroxyvitamin D(3) showed that production of autocrine growth factors interleukin (IL)-6 and IL-8 was reduced in a dose-dependent manner, whereas no effect was observed on vascular endothelial growth factor and basic fibroblast growth factor. Transcription initiated at the IL-6 promoter was repressed by VDR agonist. The DNA sequences required to mediate this repression were localized to nucleotides -225/-110 in the 5'-flanking region. The antitumor activity of VDR agonists was also confirmed in KS tumor xenograft and after topical application in patients with KS. 1alpha,25 Dihydroxyvitamin D(3) and its analogs may thus be candidates for clinical development in KS.
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PMID:Kaposi sarcoma is a therapeutic target for vitamin D(3) receptor agonist. 1105 2

Any major burn is followed by a pronounced endocrine and metabolic response, by an acute phase response. In 30 burn subjects whose bone status was studied after burn trauma with the densitometer HOLOGIC 2000, bone involvement was found 6 and 12 months postburn: the Bone Mineral Density (BMD) of their lumbar vertebrae L1-4 and of their left hip dropped significantly in most of them. Elevated levels of cortisol both in blood and in urine (free cortisol) were found, accompanied by very low testosterone, dihydrotestosterone (DHT) and free testosterone levels in blood of the burned males, but not of the females. Elevated 17beta-estradiol levels were found in many burned males; they were generally not low in the burned females. DHEA-S levels were generally low. Very low levels of the triiodothyronine (T3) and of the free thyroxine (FT4) were found. Increased, even very high, PTH values were occasionally present. hGH and IGF-1 were generally normal, with a few exceptions (low or increased levels). Total and ionized calcium levels were low after burn, 250H vitamin D (calcidiol) was usually low or low normal too. Prolonged and very high levels of CTX and of NTX (both are indicators of bone resorpcion, of collagen catabolism) were found, as well as of the ACP (acid phosphatases), but the latter were less manifest, if compared with the CTX and NTX. ALP (alkaline phosphatases) were elevated too, but their elevated levels were much less pronounced than the levels of CTX and NTX. Osteocalcin levels were initially low to low normal, to increase later to the normal levels. As for the cytokines that had been investigated, mostly the elevated levels of TNFalpha were found, as well as those of IL-2, IL-6 and IL-8. Finally, a few suggestions have been given regarding the additional possibilities how to treat the burned patients: the use of anabolics, of vitamin D, of calcium, eventually of calcitonin.
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PMID:Endocrine changes after burns: the bone involvement. 1473 53

1, 25 Dihydroxyvitamin D(3) (1, 25(OH)(2) D(3)) has gained significant importance in tuberculosis with regard to its immunoregulatory activities. Our aim was to evaluate the effect of 1, 25(OH)(2) D(3) on cytokine response to Mycobacterium tuberculosis antigens in pulmonary tuberculosis. Peripheral blood mononuclear cells obtained from 60 healthy controls and 52 pulmonary tuberculosis patients were cultured with culture filtrate antigen (CFA) of M. tuberculosis and live M. tuberculosis with and without 1, 25(OH)(2) D(3) (10(-9), 10(-8)and 10(-7)M concentrations). The culture supernatants were used to estimate IL-8, IL-6, TGF-beta, IL-10, IFN-gamma, IL-12p40, IL-2, IL-4 and IL-5 levels by ELISA. 1, 25 Dihydroxyvitamin D(3) significantly suppressed IL-12p40 and IFN-gamma production in response to CFA and live M. tuberculosis with a maximum suppression at 10(-7)M concentration (p<0.0001). In CFA stimulated cultures, addition of 1, 25(OH)(2) D(3) significantly suppressed IL-8, IL-6 and IL-10 whereas the IL-2 levels were significantly increased in controls. It variably influenced the Th2 cytokines, showing an increased trend for IL-4 and suppressed IL-5 levels. We report that 1, 25(OH)(2) D(3) differentially modulates production of cytokines in response to M. tuberculosis antigens by predominantly suppressing IL-12p40 and IFN-gamma production in a dose dependent manner. Our results suggest a role for vitamin D in restricting acquired immune response against tuberculosis by regulating cytokine production.
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PMID:1, 25 Dihydroxyvitamin D3 modulated cytokine response in pulmonary tuberculosis. 1791 Oct 26

Considering the anatomical location of the urethral meatus, it is surprising that urine is normally sterile. The defensive properties of uroepithelia help maintain this sterility as strategically necessary for long-term survival. Epithelia lining the urinary tract prevent adhesion of bacteria by release of Tamm-Horsfall protein, lactoferrin, lipocalin, and constitutive and inducible bactericidal antimicrobial peptides such as alpha- and beta-defensins and cathelicidin. Microbes that overwhelm these early defenses contact uroepithelia and activate an innate immune response through Toll-like receptor 4. With persistence of increasing numbers of microbes, chemokines (IL-8) and cytokines (IL-1 and TNFalpha) attract and activate large numbers of neutrophils and macrophages that damage tubulointerstitial parenchyma. The risk of serious infection in humans seems quite variable. Cathelicidin, for example, is a vitamin D-dependent gene, and vitamin D stores may influence susceptibility to urinary tract infection in selected individuals. As more knowledge accrues, vitamin D supplementation may someday be useful as adjuvant therapy in this setting.
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PMID:Antimicrobial peptides, innate immunity, and the normally sterile urinary tract. 1794 49

Inflammation, elicited in the skin following tissue damage or pathogen invasion, may become chronic with deleterious consequences. Tumor necrosis factor (TNF) is a key mediator of cutaneous inflammation and the keratinocyte an important protagonist of skin immunity. Calcitriol, the hormonally active vitamin D metabolite, and its analogs attenuate epidermal inflammation and inhibit the hyperproliferation of keratinocytes associated with the inflammatory disorder, psoriasis. Since activation of extracellular signal-regulated kinase (ERK) promotes keratinocyte proliferation and mediates epidermal inflammation, we studied the effect of calcitriol on ERK activation in HaCaT keratinocytes exposed to the ubiquitous inflammatory cytokine TNF. By using the EGF receptor (EGFR) tyrosine kinase inhibitor, AG1487 and the Src family inhibitor, PP-1, we established that TNF activated ERK in an EGFR and Src dependent and an EGFR and Src independent modes. EGFR dependent activation resulted in the upregulation of the transcription factor, c-Fos, while the EGFR independent activation mode was of a shorter duration, did not affect c-Fos expression but induced IL-8 mRNA expression. Pretreatment with calcitriol, enhanced TNF-induced EGFR-Src dependent ERK activation and tyrosine phosphorylation of the EGFR, but abolished the EGFR-Src independent ERK activation. These effects were mirrored by enhancement of c-Fos and inhibition of IL-8 induction by TNF. Treatment with calcitriol increased the rate of the de-phosphorylation of activated ERK, accounting for the inhibition of EGFR-Src independent ERK activation by TNF. It is possible that effects on the ERK cascade contribute to the effects of calcitriol and its synthetic analogs on cutaneous inflammation and keratinocyte proliferation.
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PMID:Two modes of ERK activation by TNF in keratinocytes: different cellular outcomes and bi-directional modulation by vitamin D. 1808 Mar 20

Lithocholic acid (LCA), a secondary bile acid, is a vitamin D receptor (VDR) ligand. 1,25-Dihydroxyvitamin D(3) (1,25(OH)(2)D(3)), the hormonal form of vitamin D, is involved in the anti-inflammatory action through VDR. Therefore, we hypothesize that LCA acts like 1,25(OH)(2)D(3) to drive anti-inflammatory signals. In present study, we used human colonic cancer cells to assess the role of LCA in regulation of the pro-inflammatory NF-kappaB pathway. We found that LCA treatment increased VDR levels, mimicking the effect of 1,25(OH)(2)D(3). LCA pretreatment inhibited the IL-1beta-induced IkappaBalpha degradation and decreased the NF-kappaB p65 phosphorylation. We also measured the production of IL-8, a well-known NF-kappaB target gene, as a read-out of the biological effect of LCA expression on NF-kappaB pathway. LCA significantly decreased IL-8 secretion induced by IL-1beta. These LCA-induced effects were very similar to those of 1,25(OH)(2)D(3.) Thus, LCA recapitulated the effects of 1,25(OH)(2)D(3) on IL-1beta stimulated cells. Mouse embryonic fibroblast (MEF) cells lacking VDR have intrinsically high NF-kappaB activity. LCA pretreatment was not able to prevent TNFalpha-induced IkappaBalpha degradation in MEF VDR (-/-), whereas LCA stabilized IkappaBalpha in MEF VDR (+/-) cells. Collectively, our data indicated that LCA activated the VDR to block inflammatory signals in colon cells.
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PMID:Lithocholic acid down-regulation of NF-kappaB activity through vitamin D receptor in colonic cancer cells. 1851 93

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