Pentanoic acid induces thymic stromal lymphopoietin production through Gq/11 and Rho-associated protein kinase signaling pathway in keratinocytes.

Thymic stromal lymphopoietin (TSLP) plays an important role in allergic skin inflammation. Short-chain fatty acids (SCFAs), including pentanoic acid, are products of bacterial metabolism and are associated with allergic skin disorders. However, whether SCFAs induce TSLP production is still unclear. In this study, we evaluated the effect of SCFAs on TSLP production and found that pentanoic acid was the most efficacious of the tested SCFAs. The Gq/11 inhibitor YM-254890 and the Rho-associated protein kinase (ROCK) inhibitor Y-27632 inhibited pentanoic acid-induced TSLP production, as did transfection with Gq/11 siRNA. These results suggested that pentanoic acid-induced TSLP production was mediated by Gq/11 and ROCK, providing insights into a novel TSLP production pathway in keratinocytes. The novel mechanism of TSLP production is expected to support the development of TSLP-regulating approaches in allergic skin disorders.

Identification of a cell line producing high levels of TSLP: advantages for screening of anti-allergic drugs.

Thymic stromal lymphopoietin (TSLP) plays critical roles in the induction and exacerbation of allergic diseases. These findings suggest that an inhibitor of TSLP production may be a novel drug for allergic diseases. However, conducting high-throughput screening of such compounds is difficult because there is currently no appropriate in vitro system. In the present study, we demonstrated that the mouse keratinocyte cell line KCMH-1 produced higher amounts of TSLP than the mouse keratinocyte cell line PAM-212, human keratinocyte cell line HaCaT, or bronchial cell line BEAS-2B. A reporter gene assay revealed that transcriptional activity of the TSLP gene was also markedly higher in KCMH-1 than in PAM212 cells. Both dexamethasone and the retinoid X receptor agonist HX600 inhibited the production of TSLP in KCMH-1 cells, which indicated that its production could be pharmacologically regulated. Moreover, the biological activity of TSLP released from KCMH-1 cells in the medium was endorsed by the induction of OX40L expression in bone marrow-derived dendritic cells. These results indicate that KCMH-1 can be utilized in high-throughput screening of inhibitors of TSLP production and also as a source of native TSLP.

Induction of thymic stromal lymphopoietin production by nonanoic acid and exacerbation of allergic inflammation in mice.

BACKGROUND: Thymic stromal lymphopoietin (TSLP) plays critical roles in the induction and exacerbation of allergic diseases. We tested various chemicals in the environment and found that xylene and 1,2,4-trimethylbenzene induced the production of TSLP in vivo. These findings prompted us to search for additional chemicals that induce TSLP production. In this study, we examined whether fatty acids could induce the production of TSLP in vivo and exacerbate allergic inflammation. METHODS: Various fatty acids and related compounds were painted on the ear lobes of mice and the amount of TSLP in the homogenate of ear lobe tissue was determined. The effects of nonanoic acid on allergic inflammation were also examined. RESULTS: Octanoic acid, nonanoic acid, and decanoic acid markedly induced TSLP production, while a medium-chain aldehyde and alcohol showed only weak activity. Nonanoic acid induced the production of TSLP with a maximum at 24 h. TSLP production was even observed in nonanoic acid-treated C3H/HeJ mice that lacked functional toll-like receptor 4. The aryl hydrocarbon receptor agonist ß-naphthoflavone did not induce TSLP production. Nonanoic acid promoted sensitization to ovalbumin, resulting in an enhancement in the cutaneous anaphylactic response. In addition, painting of nonanoic acid after the sensitization augmented picryl chloride-induced thickening of the ear, which was reversed in TSLP receptor-deficient mice. CONCLUSIONS: Nonanoic acid and certain fatty acids induced TSLP production, resulting in the exacerbation of allergic inflammation. We propose that TSLP-inducing chemical compounds such as nonanoic acid be recognized as chemical allergo-accelerators.

Common variants in MAGI2 gene are associated with increased risk for cognitive impairment in schizophrenic patients.

Schizophrenia is a complex psychiatric disorder characterized by positive symptoms, negative symptoms, and cognitive impairment. MAGI2, a relatively large gene (∼1.5 Mbps) that maps to chromosome 7q21, is involved in recruitment of neurotransmitter receptors such as AMPA- and NMDA-type glutamate receptors. A genetic association study designed to evaluate the association between MAGI2 and cognitive performance or schizophrenia has not been conducted. In this case-control study, we examined the relationship of single nucleotide polymorphism (SNP) variations in MAGI2 and risk for schizophrenia in a large Japanese sample and explored the potential relationships between variations in MAGI2 and aspects of human cognitive function related to glutamate activity. Based on the result of first schizophrenia genome-wide association study in a Japanese population (JGWAS), we selected four independent SNPs and performed an association study using a large independent Japanese sample set (cases 1624, controls 1621). Wisconsin Card Sorting Test (WCST) was used to evaluate executive function in 114 cases and 91 controls. We found suggestive evidence for genetic association of common SNPs within MAGI2 locus and schizophrenia in Japanese population. Furthermore in terms of association between MAGI2 and cognitive performance, we observed that genotype effect of rs2190665 on WCST score was significant (p = 0.034) and rs4729938 trended toward significance (p = 0.08). In conclusion, although we could not detect strong genetic evidence for association of common variants in MAGI2 and increased schizophrenia risk in a Japanese population, these SNPs may increase risk of cognitive impairment in schizophrenic patients.

Screening genes that change expression during compression wood formation in Chamaecyparis obtusa.

We screened cDNA fragments that change their expression during compression wood formation by fluorescent differential display (FDD) in five adult trees (Chamaecyparis obtusa (Siebold & Zucc.) Endl.) growing naturally at an angle to the vertical, and in two saplings, one vertical, the other inclined. We conducted anatomical observations and measurements of the released strain of growth stress on the five adult trees to confirm that they formed compression wood on the lower side of the inclined trunks. Based on sequencing results from selected cDNA fragments, we conducted homology searches of the GenBank database and designed specific primers for the 67 screened fragments. Using these primers and different saplings from those used for the FDD screening, we tested the expression levels of each fragment in normal, compression and opposite wood regions of saplings by semiquantitative reverse-transcription polymerase chain reaction. Twenty-four fragments showed reproducible expression patterns, indicating that these fragments changed their expression during compression wood formation. Some fragments showed differential expression between the apical and basal regions of the lower side of the inclined stem in the region of compression wood formation. Anatomical observations indicated more intense compression wood formation in the basal region than in the apical region of the stem, demonstrating a relationship between compression wood development and gene expression.

Escherichia coli cytosolic glycerophosphodiester phosphodiesterase (UgpQ) requires Mg2+, Co2+, or Mn2+ for its enzyme activity.

Escherichia coli cytosolic glycerophosphodiester phosphodiesterase, UgpQ, functions in the absence of other proteins encoded by the ugp operon and requires Mg2+, Mn2+, or Co2+, in contrast to Ca2+-dependent periplasmic glycerophosphodiester phosphodiesterase, GlpQ. UgpQ has broad substrate specificity toward various glycerophosphodiesters, producing sn-glycerol-3-phosphate and the corresponding alcohols. UgpQ accumulates under conditions of phosphate starvation, suggesting that it allows the utilization of glycerophosphodiesters as a source of phosphate. These results clarify how E. coli utilizes glycerophosphodiesters using two homologous enzymes, UgpQ and GlpQ.

Stem-righting mechanism in gymnosperm trees deduced from limitations in compression wood development.

BACKGROUND AND AIMS: In response to inclination stimuli, gymnosperm trees undergo corrective growth during which compression wood develops on the lower side of the inclined stem. High compressive growth stress is generated in the compression wood region and is an important factor in righting the stem. The aims of the study were to elucidate how the generation of compressive growth stress in the compression wood region is involved in the righting response and thus to determine a righting mechanism for tree saplings. METHODS: Cryptomeria japonica saplings were grown at inclinations of 0 degrees (vertical) to 50 degrees. At each inclination angle, the growth stress on the lower side of the inclined stem was investigated, together with the degree of compression-wood development such as the width of the current growth layer and lignin content, and the upward bending moment. KEY RESULTS: Growth stress, the degree of compression wood development, and the upward moment grew as the stem inclination angle increased from 0 to 30 degrees, but did not rise further at inclinations > 30 degrees. CONCLUSIONS: The results suggest the following righting mechanism for gymnosperm saplings. As the stem inclination is elevated from 0 to 30 degrees, the degree of compression wood development increases to force the sapling back to its original orientation; at inclinations > 30 degrees, the maximum degree of compression wood is formed and additional time is needed for the stem to reorient itself.