Toll-like receptor 2 (TLR2) gene polymorphisms are not associated with sarcoidosis in the Japanese population.

PURPOSE: Sarcoidosis is a systemic inflammatory disease characterized by the formation of non-caseating granulomas, with varied clinical manifestations. The common etiology of sarcoidosis is uncertain, but it is thought to be triggered by an exogenous antigenic stimulus, such as some bacterial proteins. Toll-like receptors (TLRs) recognize microbial components and elicit innate as well as adaptive immune responses. It has been reported that polymorphisms in TLR2 might be important in a small group of Caucasian sarcoidosis patients. The present study aimed to establish whether these findings are relevant to the Japanese population. METHODS: We genotyped 5 single-nucleotide polymorphisms (SNPs) in TLR2 and assessed the allelic diversity between 257 Japanese sarcoidosis patients and 193 Japanese healthy controls. RESULTS: No significant differences in the frequency of TLR2 alleles and haplotypes in the sarcoidosis cases were found in comparison with the controls. However, marginal associations were observed for TLR2 at rs3804099 and rs3804100 in sarcoidosis patients with cutaneous manifestations. CONCLUSIONS: Our results suggest that TLR2 polymorphisms are not significantly related to the pathogenesis of sarcoidosis in the Japanese population.

Dietary protein level and dietary interaction affect quinolinic acid concentration in rats.

During tryptophan-niacin conversion, hepatic alpha-amino-beta-carboxymuconate-epsilon-semialdehyde decarboxylase (ACMSD) [EC4.1.1.45] plays a key role in regulating NAD biosynthesis. ACMSD activity is greatly affected by many factors such as nutritional status and disease. The tryptophan catabolite quinolinic acid has been reported to be associated with the pathogenesis of various disorders and is a potential endogenous toxin. However the effects of dietary protein levels or dietary interaction between protein levels and fatty acid type to this process have not been investigated and are still unknown. In this study, we examined whether dietary protein level, fatty acid type, namely saturated fatty acid and polyunsaturated fatty acid, and their interaction affect serum quinolinic acid concentration in rats. Male Sprague-Dawley rats (4-weeks old) were fed with 20% casein + 10% stearic acid diet (20C10S), 20% casein + 10% linoleic acid diet (20C10L), 40% casein + 10% stearic acid diet (40C10S), or 40% casein + 10% linoleic acid diet (40C10L) for 8 days, and serum quinolinic acid concentration and ACMSD activity were determined. Serum quinolinic acid concentration was significantly increased in the 40C10L group compared with other three groups. There was also the negative correlation between the sum of liver and kidney ACMSD activities, and serum quinolinic acid concentration per tryptophan intake (r = 0.8209, p < 0.01). Increased serum QA concentrations are probably due to a decreased ACMSD activity.

Differential effects of pyrazinamide and clofibrate on gene expression of rat hepatic alpha-amino-beta-carboxymuconate-epsilon-semialdehyde decarboxylase, a key enzyme of the tryptophan-NAD pathway.

Hepatic alpha-amino-beta-carboxymuconate-epsilon-semialdehyde decarboxylase (ACMSD) [EC4.1.1.45] plays a key role in regulating NAD biosynthesis from tryptophan. The aim of this study was to evaluate the ACMSD mRNA expression after pyrazinamide or peroxisome proliferators ingestion. When rats were fed a control (pyrazinamide- and clofibrate-free) diet, 1% pyrazinamide- or 0.24% clofibrate-containing diets for 8 days, hepatic ACMSD activity and mRNA in rats consuming the clofibrate-containing diet was strongly suppressed, as compared with those fed the control and pyrazinamide diet. Pyrazinamide suppressed liver and kidney ACMSD activities, but did not affect ACMSD mRNA. Blood NAD was increased in the clofibrate and pyrazinamide groups. Shifting from the control diet to a clofibrate diet suppressed ACMSD mRNA strongly at day 1 and continued through day 4. However ACMSD activity decreased gradually. In rats fed with several kinds of peroxisome-proliferator-containing diets such as phthalate ester, bezafibrate, Wy-14,643, 2-(-4-chlorophenoxy) propionic acid, or dehydroisoandrosterone for 8 days, hepatic ACMSD mRNA was drastically decreased by all the peroxisome proliferators. These results suggest that the transcription level of hepatic ACMSD is modulated by peroxisome proliferators, and the fluctuation of the hepatic ACMSD mRNA expression was followed by that of the ACMSD activity. However, pyrazinamide does not affect the transcription level of hepatic ACMSD.

Differential effects of dietary fatty acids on rat liver alpha-amino-beta-carboxymuconate-epsilon-semialdehyde decarboxylase activity and gene expression.

Hepatic alpha-amino-beta-carboxymuconate-epsilon-semialdehyde decarboxylase (ACMSD; formerly termed picolinic carboxylase) [EC4.1.1.45] plays a key role in regulating NAD biosynthesis and the generation of quinolinate (quinolinic acid) from tryptophan. Quinolinate is a potent endogenous excitotoxin of neuronal cells. We previously reported that ingestion of fatty acids by rats leads to a decrease in their hepatic ACMSD activity. However, the mechanism of this phenomenon is not clarified. We previously purified ACMSD and cloned cDNA encoding rat ACMSD. Therefore, in this study, we examined the differential effect of fatty acids on ACMSD mRNA expression by Northern blot. Moreover, we measured quinolinic acid concentration in rats fed on fatty acid. When diets containing 2% level of fatty acid were given to male Sprague-Dawley rats (4 weeks old) for 8 days, long-chain saturated fatty acids and oleic acid did not affect ACMSD mRNA expression in the liver. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) strongly suppressed the liver ACMSD mRNA expression. In rats fed with high linoleic acid diet for 8 days, serum quinolinic acid was significantly increased as compared with the rats fed on a fatty acid-free diet under the condition of the approximately same calorie ingestion. These results suggest that the transcription level of ACMSD is modulated by polyunsaturated fatty acids, and suppressive potency of ACMSD mRNA is n-3 fatty acid family>linoleic acid (n-6 fatty acid)>saturated fatty acid. Moreover, this study provides the information that a high polyunsaturated fatty acid diet affects the production of quinolinic acid in serum by suppressing the ACMSD activity.