Citations

Corticosteroids (CSs) are commonly used to manage wheezing and asthma in pediatric populations. Although corticosteroids are effective in alleviating airway diseases, some children with more moderate-severe asthma phenotypes show CS resistance and exhibit significant airflow obstruction, persistent inflammation, and more frequent exacerbations. Previous studies have demonstrated that Th1 cytokines, such as TNF-α and IFN-γ, promote CS resistance in adult human airway smooth muscle (ASM). In the present study, using a human fetal ASM cell model, we tested the hypothesis that TNF-α/IFN-γ induces CS resistance. In contrast to TNF-α or IFN-γ alone, the combination of TNF-α/IFN-γ blunted the ability of fluticasone propionate (FP) to reduce expression of the chemokines CCL5 and CXCL10 despite expression of key anti-inflammatory glucocorticoid receptor target genes being largely unaffected by TNF-α/IFN-γ. Expression of the NF-κB subunit p65 and phosphorylation of Stat1 were elevated in cells treated with TNF-α/IFN-γ, an effect that remained in the presence of FP. siRNA knockdown studies demonstrated the effects of TNF-α/IFN-γ on increased p65 are mediated by Stat1, a transcription factor activated by IFN-γ. Expression of TNFAIP3, a negative regulator of NF-κB activity, was not altered by TNF-α/IFN-γ. However, the effects of TNF-α/IFN-γ were partially reduced by overexpression of TNFAIP3 but did not influence p65 expression. Together, these data suggest that IFN-γ augments the effects of TNF-α on chemokines by enhancing expression of key inflammatory pathways in the presence of CS. Interactions between TNF-α- and IFN-γ-mediated pathways may promote inflammation in asthmatic children resistant to CSs.

Introduction: Genome-wide association (GWA) studies have contributed substantially to the understanding of complex vascular traits including ischemic stroke; however, genetic determinants of acute cerebral ischemia remain to be elucidated. Objective: To investigate the genetic architecture of cerebral infarct lesion burden in patients with acute ischemic stroke (AIS). Methods: Twelve international sites contributed 3,301 AIS subjects with acute MRI and genome-wide genotyping to the MRI-GENIE study. In a preliminary analysis of 657 subjects of European ancestry, acute cerebral infarct lesions were outlined on diffusion-weighted images (DWI) using a semi-automated volumetric method. Standard quality control measures were performed per single nucleotide polymorphism (SNP) and per subject. SNPs were imputed to the Haplotype Reference Consortium v1.1 panel. Natural log-transformed DWI volume was used for GWA analysis with allelic dosage per SNP, age, sex and principal components 1-5 of genetic ancestry as covariates. Results: GWA testing for DWI volume in 7.7 million SNPs yielded no signal crossing the Bonferroni-corrected genome-wide significance threshold of p <5*10 -8 . However, several loci passed the nominal significance threshold of p <1*10 -6 (Figure 1), including a locus on chromosome 2 in the SPATA3-AS1 (spermatogenesis associated 3 antisense RNA 1) gene (lead SNP: rs2368999, MAF=36%, p =8.4*10 -7 ) and an intronic locus on chromosome 10 in the ATRNL1 (Attractin like 1) gene (lead SNP: rs592284, MAF=10%, p =9.1*10 -7 ). Conclusion: In this first-to-date, preliminary GWAS of acute cerebral infarct volume in AIS patients, we identified several new, nominally significant loci including a locus in ATRNL1, a gene previously linked to carotid plaque burden. Further analyses of the MRI-GENIE cohort to replicate these findings, to include stroke subtype specific analyses, and to increase the overall statistical power of the study are ongoing.