Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.7.6 (RNA polymerase)
 34,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Inflammation in the gastrointestinal tract is associated with increased epithelial cell proliferation. Keratinocyte growth factor (KGF) is an epithelial cell mitogen widely expressed by mesenchymal cells subjacent to the epithelial cells. In this study, we have investigated the expression and distribution of KGF in normal and diseased (Crohn's disease and ulcerative colitis(UC)) intestine by quantitative competitive reverse-transcriptase polymerase chain reaction in whole biopsies and purified lamina propria myofibroblasts and by in situ hybridization. Analysis of whole mucosal biopsies reveals significantly higher numbers of KGF mRNA transcripts in UC compared with Crohn's colitis and control colon (P < 0.001). KGF transcripts were also elevated in Crohn's ileitis compared with normal ileum. In situ hybridization showed a marked increase in cells expressing KGF mRNA throughout the lamina propria in both UC and Crohn's tissue. In Crohn's disease, positively hybridizing cells were only rarely seen in the submucosa but were abundant around the bases of the crypts and were not associated with lymphoid aggregates. In purified mucosal myofibroblasts, increased (15- to 20-fold) KGF mRNA expression was seen in UC compared with control and Crohn's tissue. These results confirm and extend earlier studies showing that KGF transcripts are elevated in inflammatory bowel disease, but they show for the first time that transcripts are higher in UC than Crohn's disease because of increased production by mucosal mesenchymal cells.
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PMID:Keratinocyte growth factor in inflammatory bowel disease. Increased mRNA transcripts in ulcerative colitis compared with Crohn's disease in biopsies and isolated mucosal myofibroblasts. 935 73

The receptor for hyaluronan (HA)-mediated motility (RHAMM) controls motility by malignant cells in myeloma and is abnormally expressed on the surface of most malignant B and plasma cells in blood or bone marrow (BM) of patients with multiple myeloma (MM). RHAMM cDNA was cloned and sequenced from the malignant B and plasma cells comprising the myeloma B lineage hierarchy. Three distinct RHAMM gene products, RHAMMFL, RHAMM-48, and RHAMM-147, were cloned from MM B and plasma cells. RHAMMFL was 99% homologous to the published sequence of RHAMM. RHAMM-48 and RHAMM-147 variants align with RHAMMFL, but are characterized by sequence deletions of 48 bp (16 amino acids [aa]) and 147 bp (49 aa), respectively. The relative frequency of these RHAMM transcripts in MM plasma cells was determined by cloning of reverse-transcriptase polymerase chain reaction (RT-PCR) products amplified from MM plasma cells. Of 115 randomly picked clones, 49% were RHAMMFL, 47% were RHAMM-48, and 4% were RHAMM-147. All of the detected RHAMM variants contain exon 4, which is alternatively spliced in murine RHAMM, and had only a single copy of the exon 8 repeat sequence detected in murine RHAMM. RT-PCR analysis of sorted blood or BM cells from 22 MM patients showed that overexpression of RHAMM variants is characteristic of MM B cells and BM plasma cells in all patients tested. RHAMM also appeared to be overexpressed in B lymphoma and B-chronic lymphocytic leukemia (CLL) cells. In B cells from normal donors, RHAMMFL was only weakly detectable in resting B cells from five of eight normal donors or in chronically activated B cells from three patients with Crohn's disease. RHAMM-48 was detectable in B cells from one of eight normal donors, but was undetectable in B cells of three donors with Crohn's disease. RHAMM-147 was undetectable in normal and Crohn's disease B cells. In situ RT-PCR was used to determine the number of individual cells with aggregate RHAMM transcripts. For six patients, 29% of BM plasma cells and 12% of MM B cells had detectable RHAMM transcripts, while for five normal donors, only 1. 2% of B cells expressed RHAMM transcripts. This work suggests that RHAMMFL, RHAMM-48, and RHAMM-147 splice variants are overexpressed in MM and other B lymphocyte malignancies relative to resting or in vivo-activated B cells, raising the possibility that RHAMM and its variants may contribute to the malignant process in B-cell malignancies such as lymphoma, CLL, and MM.
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PMID:Overexpression of the receptor for hyaluronan-mediated motility (RHAMM) characterizes the malignant clone in multiple myeloma: identification of three distinct RHAMM variants. 1002 98

Several observations suggest that bacteria induce autoimmunity in primary biliary cirrhosis (PBC). Since no PBC-specific bacterial species could be identified, it can be speculated that the triggers are non-species-specific bacterial proteins. This hypothesis would imply that several or even all bacterial species can trigger PBC. Therefore, we investigated whether PBC exhibits immune reactions to non-species-specific bacterial antigens. Yersinia enterocolitica O3 was screened for the presence of proteins that were labeled by immunoblotting using PBC sera. We focused our investigations on a 160-kDa protein, which was further enriched and characterized by partial N-terminal amino acid sequencing. The prevalence of antibodies to this protein was determined by immunoblotting in a variety of diseases. The 160-kDa protein was identified as the beta-subunit of bacterial RNA-polymerase, a highly conserved bacterial protein with a very high degree of sequence identity among all bacterial species. Antibodies to the beta-subunit of bacterial RNA polymerase were specific for this protein. Until now no mammalian protein could be found that cross-reacts with these antibodies. The prevalence of antibodies to the beta-subunit of bacterial RNA polymerase (ARPA) using the protein from Yersinia enterocolitica O3 (serum dilution 1:1000) was: healthy controls (HC, N = 101) 7.9%, primary biliary cirrhosis (PBC, N = 61) 32.8%, autoimmune hepatitis type 1 (AIH, N = 46) 26.1%, alcoholic liver cirrhosis (ALC, N = 44) 9.1%, Crohn's disease (CD, N = 38) 7.9%, ulcerative colitis (UC, N = 24) 8.3%, primary sclerosing cholangitis + UC (PSC/UC, N = 11) 0%, acute yersiniosis (Yers, N = 36) 19.4%, acute infection with Campylobacter jejuni (Camp, N = 10) 0%, acute Q-fever (QF, N = 16) 6.25%, chronic hepatitis C (HCV, N = 39) 7.7%, c-ANCA-positive vasculitis (Vasc, N = 40) 15%, systemic lupus erythematosus (SLE, N = 28) 10.7%, and malaria tropica (MT, N = 24) 16.7%. There was no significant difference between PBC and AIH. The group of autoimmune liver diseases (PBC + AIH, N = 107, 29.9%) differed highly significantly from HC, chronic inflammatory bowel diseases (CD + UC + PSC/UC, N = 73, 6.8%), ALC, and HCV and also differed significantly (P = 0.01) from the group with bacterial and parasitic diseases (Yers + Camp + QF + MT, N = 86,13.95%) and from the group with Vasc + SLE (N = 68,13.2%). Testing of ARPA using the protein from E. coli yielded nearly identical results. In conclusion, an increased prevalence of antibodies to the beta-subunit of bacterial RNA polymerase, a highly conserved non-species-specific bacterial protein, can be found in primary biliary cirrhosis, but also in autoimmune hepatitis type I. These findings do not add an argument for a bacterial trigger of PBC. Rather, they suggest that ARPA belong to the pool of natural antibodies that are up-regulated in autoimmune liver diseases.
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PMID:Identification of beta-subunit of bacterial RNA-polymerase--a non-species-specific bacterial protein--as target of antibodies in primary biliary cirrhosis. 1275 71

Overexpression of multidrug resistance (MDR) protein, P-glycoprotein (P-gp), on lymphocytes has been suggested to be implicated in the failure of glucocorticoid (GC) therapy in patients with ulcerative colitis (UC). However, whether the overexpression of P-gp in a class of patients with inflammatory bowel disease (IBD) is intrinsic or related to the administration of GC is unknown. Relative amounts of MDR1 mRNA expressed in peripheral blood mononuclear cells (PBMCs) were measured using the reverse-transcriptase polymerase chain reaction (RT-PCR) technique in 25 UC patients having no history of GC administration, 25 UC patients having experienced GC therapy, 19 patients with Crohn's disease (CD) with no history of GC therapy, and 27 healthy subjects. Relative amounts of MDR1 mRNA expressed in PBMCs were compared among the groups. The relationship between the amounts of MDR1 mRNA expressed, as well as the total dose of GC administered or the period of GC therapy in UC patients, was examined. The relative amounts of MDR1 mRNA expressed in PBMCs were not significantly different between the healthy subjects and CD patients or UC patients having no history of GC therapy. However, the mean MDR1 mRNA amount in PBMCs of UC patients having experienced GC therapy was significantly greater than that in PBMCs of UC patients with no history of GC administration (p = 0.0375). The amounts of MDR1 mRNA in PBMCs of UC patients having experienced GC therapy significantly correlated with the total dose of GCs administered (p = 0.0175). Overexpression of MDR1 mRNA in PBMCs of IBD patients is not intrinsic. However, high-dose administration of GCs for the treatment of UC may result in an increased expression of MDR1 mRNA, which may impair successful GC therapy in these patients.
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PMID:MDR1 mRNA expressions in peripheral blood mononuclear cells of patients with ulcerative colitis in relation to glucocorticoid administration. 1510 68

Targeted inhibition of tumour necrosis factor-alpha (TNF-alpha) is an effective therapy in rheumatoid arthritis and Crohn's disease (CD). Infliximab, a monoclonal murine-human chimeric antibody to TNF-alpha, and etanercept, a fusion protein of two p75 chains of the TNF receptor II and the Fc portion of IgG1, are generally well tolerated. Rarely does clinically significant autoimmunity, including drug-induced lupus and vasculitis occur. Immunologic mechanisms underlying the development of autoimmunity in the presence of such powerful immunosuppressants are unknown. We describe a patient with CD, who developed cutaneous vasculitis on etanercept, which worsened significantly with switch to infliximab. Investigation of the associated systemic and local immune response demonstrated the absence of human antichimera antibodies, but mRNA for T-helper 1 cytokines, chemokines and defensins in the skin and elevated angiogenesis factors in the serum, as determined by reverse-transcriptase polymerase chain reaction and enzyme-linked immunosorbent assay. Histopathology revealed a lymphocytic vasculitis composed of T cells. A permanent B-cell line (MD-B) producing extremely high amounts of chemokines and interleukin-6 was established from this patient's peripheral blood. Lesions progressed despite discontinuation of the drugs and (40 mg/day) prednisone but almost completely resolved with single dose of (0.1 mg/kg) intravenous dexamethasone, which may be therapy of choice for this reaction. A few lesions (<10) have recurred intermittently over 4 years of follow-up, suggesting possible persistence of this TNF-inhibitor-triggered autoimmune disease.
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PMID:Immunology of cutaneous vasculitis associated with both etanercept and infliximab. 1585 15

Macrophages (MPs) produce increased levels of proinflammatory cytokines in Crohn's disease; these cytokines are thought to play a central role in the occurrence of the disease. Biologics are currently available for anti-cytokine therapy, but treating intestinal inflammation through direct suppression of proinflammatory cytokine production could be more effective. P-ATPase inhibitors have been reported to be anti-inflammatory, and these inhibitors might suppress the production of MP proinflammatory cytokines. In this study, we examined the effect of two types of ATPase inhibitors on the expression patterns of typical proinflammatory cytokines. Peritoneal MPs from 6- to 8-week-old mice were cultured for 48 h in the presence of lansoprazole (P-ATPase inhibitor), bafilomycin A(1) (V-ATPase inhibitor), or the control solvent dimethylsulfoxide. The MPs were then examined for cytokine expression by quantitative real-time polymerase chain reaction (PCR), and culture supernatants were examined for cytokine production with a multiplex assay in a suspension array system. The possible existence of P-ATPase mRNA in MPs was explored using reverse-transcriptase PCR. P-ATPase mRNA was not detected in MP cells. However, all examined proinflammatory cytokines decreased significantly in their mRNA and protein expression in the lansoprazole-treated group. Conversely, bafilomycin A(1) increased the levels of these cytokines. Lansoprazole might be useful for the treatment of inflammatory bowel diseases (IBDs), including Crohn's disease, as it suppresses the production of relevant MP proinflammatory cytokines. However, because P-ATPase was not detected in MPs, the mechanism is unclear and remains to be studied further in an IBD animal model.
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PMID:Suppression of proinflammatory cytokine production in macrophages by lansoprazole. 1693 10

In this case report, we describe a 63-year-old female with Crohn's disease since age 16 years, and on adalimumab therapy, who inadvertently received a yellow fever vaccine (YFV) 4 days before her next dose of adalimumab. She had never received YFV. Her next dose of tumor necrosis factor (TNF) antagonist was held. She did not report any adverse effects referable to the vaccine. Reverse transcriptase-polymerase chain reaction (RT-PCR) for yellow fever (YF) viral RNA on days 12 and 18 postvaccination was negative. Neutralizing antibody to YF virus vaccine was immunoprotective on day 18 following vaccination, which further increased by day 26. A neutralizing antibody obtained 2 years following vaccination also remained immunoprotective.
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PMID:Yellow Fever Vaccination of a Primary Vaccinee During Adalimumab Therapy. 2592 88