Tristetraprolin (TTP) is an inducible, tandem zinc-finger mRNA binding protein that binds to adenylate-uridylate-rich elements (AREs) in the 3′-untranslated regions (3′UTRs) of specific mRNAs, such as that encoding TNF, and increases their rates of deadenylation and turnover. Stabilization of Tnf mRNA and other cytokine transcripts in TTP-deficient mice results in the development of a profound, chronic inflammatory syndrome characterized by polyarticular arthritis, dermatitis, myeloid hyperplasia, and autoimmunity. To address the hypothesis that increasing endogenous levels of TTP in an intact animal might be beneficial in the treatment of inflammatory diseases, we generated a mouse model (TTPΔARE) in which a 136-base instability motif in the 3′UTR of TTP mRNA was deleted in the endogenous genetic locus. These mice appeared normal, but cultured fibroblasts and macrophages derived from them exhibited increased stability of the otherwise highly labile TTP mRNA. This resulted in increased TTP protein expression in LPS-stimulated macrophages and increased levels of TTP protein in mouse tissues. TTPΔARE mice were protected from collagen antibody-induced arthritis, exhibited significantly reduced inflammation in imiquimod-induced dermatitis, and were resistant to induction of experimental autoimmune encephalomyelitis, presumably by dampening the excessive production of proinflammatory mediators in all cases. These data suggest that increased systemic levels of TTP, secondary to increased stability of its mRNA throughout the body, can be protective against inflammatory disease in certain models and might be viewed as an attractive therapeutic target for the treatment of human inflammatory diseases.AU-rich elements | mRNA stability | inflammation | deadenylation T ristetraprolin (TTP) is the prototype of a small family of RNA binding proteins that can bind to adenylate-uridylate (AU)-rich elements (AREs) in the 3′-UTR (3′UTR) of its target mRNAs and promote their rapid turnover (1, 2). TTP-deficient mice developed a chronic systemic inflammatory syndrome (3) that was prevented by interfering with the action of TNF (3-5). Tnf mRNA was then identified as a direct target of TTP-mediated destabilization (4, 6); its increase in stability in the TTP KO mice leads to the commensurate overproduction of TNF protein (4, 5).TTP mRNA expression exhibits a pattern characteristic of immediate-early response genes in several cell types, with low-toundetectable levels of expression under basal conditions, and a rapid and transient induction upon stimulation (4,7,8). The transient nature of this induction is largely due to the instability of the TTP mRNA itself, part of which is thought to be due to AREs located within the 3′UTR of TTP mRNA (4,8,9). Indeed, TTP has been suggested to bind to its own AREs and autoregulate its expression through a negative feedback loop (9). Although expression of TTP protein in these systems is also rapidly inducible, the protein is more stable than the mRNA after induction, often persisting at high level...
4-Methylimidazole (4MI) is used in the manufacture of pharmaceuticals, photographic chemicals, dyes and pigments, cleaning and agricultural chemicals, and rubber. It has been identified as a by-product of fermentation in foods and has been detected in mainstream and side stream tobacco smoke. 4MI was studied because of its high potential for human exposure. Groups of 50 male and 50 female F344/N rats were fed diets containing 0-, 625-, 1,250-, or 2,500 ppm 4MI (males) or 0-, 1,250-, 2,500-, or 5,000 ppm 4MI (females) for 106 weeks. Based on the food consumption the calculated average daily doses were approximately 30, 55, or 115 mg 4MI/kg body weight to males and 60, 120, or 250 mg 4MI/kg to females. Survival of all exposed groups of males and females was similar to that of the control groups. The mean body weights of males in the 1,250- and 2,500 ppm groups and females in the 2,500- and 5,000 ppm groups were less than those of the control groups throughout the study. Feed consumption by 5,000 ppm females was less than that by the controls. Clonic seizures, excitability, hyperactivity, and impaired gait were observed primarily in 2,500- and 5,000 ppm females. The incidence of mononuclear cell leukemia in the 5,000 ppm females was significantly greater than that in the controls. The incidences of hepatic histiocytosis, chronic inflammation, and focal fatty change were significantly increased in all exposed groups of male and female rats. The incidences of hepatocellular eosinophilic and mixed cell foci were significantly increased in 2,500 ppm males and 5,000 ppm females. Groups of 50 male and 50 female B6C3F1 mice were fed diets containing 0-, 312-, 625-, or 1,250 ppm 4MI for 106 weeks. Based on the food consumption the calculated average daily doses were approximately 40, 80, or 170 mg 4MI/kg body weight to males and females. Survival of all exposed groups of males and females was similar to that of the control groups. Mean body weights of males and females in the 1,250 ppm groups and that in the 312- and 625 ppm females were less than those of the control groups. Feed consumption by exposed groups of male and female mice was similar to that by the controls. The incidences of alveolar/bronchiolar adenoma in all exposed groups of females, alveolar/bronchiolar carcinoma in 1,250 ppm males, and alveolar/bronchiolar adenoma or carcinoma (combined) in 1,250 ppm males and 625- and 1,250 ppm females were significantly greater than those in the control groups. The incidence of alveolar epithelial hyperplasia was significantly increased in the 1,250 ppm females. 4MI is carcinogenic inducing alveolar/bronchiolar adenoma and carcinoma in male and female mice. 4MI may also induce mononuclear cell leukemia in female rats.
Chemically induced renal neoplasms in male rats, developed coincident with α 2u -globulin nephropathy, are not considered predictive of risk to humans by the International Agency for Research on Cancer (IARC) and the U.S. Environmental Protection Agency. Criteria have been defined to establish the role of α 2u -globulin nephropathy in renal carcinogenesis, based on a proposed mode of action involving sustained tubular cell proliferation resulting from α 2u -induced nephropathy, with consequent development of neoplastic lesions. Recent NTP studies demonstrated inconsistencies with this proposed mechanism, including in some cases, far weaker kidney tumor responses than expected based on the extent of α 2u -globulin nephropathy. NTP studies with decalin, propylene glycol mono-t-butyl ether and Stoddard solvent IIC included extended evaluations of α 2u -related nephropathy, and were thus used in assessing the linkage between key events in 90-day studies with renal tumors in 2-year studies. This review revealed no or at best weak associations of tumor responses with renal α 2u -globulin concentrations, indices of cell turnover, or microscopic evidence of α 2u -associated nephropathy in prechronic studies. While tumor responses corresponded somewhat with a measure of cumulative α 2u -associated nephropathy (linear mineralization of the papilla) at the end of the 2-year studies, the severity of chronic nephropathy was generally in best agreement with the pattern of tumor response. These results suggest that while α 2u -globulin nephropathy may contribute to the renal tumor response, the critical component(s) of the nephropathy most closely associated with the development of tumors could not be clearly identified in this review.
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