Release Of Cytokine Mediators Research Articles

Gene-Based Variant Analysis of Whole-Exome Sequencing in Relation to Eosinophil Count.

Eosinophils play important roles in the release of cytokine mediators in response to inflammation. Many associations between common genetic variants and eosinophils have already been reported, using single nucleotide polymorphism (SNP) array data. Here, we have analyzed 200,000 whole-exome sequences (WES) from the UK Biobank cohort and performed gene-based analyses of eosinophil count. We defined five different variant weighting schemes to incorporate information on both deleteriousness and frequency. A total of 220 genes in 55 distinct (>10 Mb apart) genomic regions were found to be associated with eosinophil count, of which seven genes (ALOX15, CSF2RB, IL17RA, IL33, JAK2, S1PR4, and SH2B3) are driven by rare variants, independent of common variants identified in genome-wide association studies. Two additional genes, NPAT and RMI1, have not been associated with eosinophil count before and are considered novel eosinophil loci. These results increase our knowledge about the effect of rare variants on eosinophil count, which can be of great value for further identification of therapeutic targets.

Abstract 419: Cytokine-Mediated Release of Vascular Endothelial Growth Factor and Stromal-Derived Factor 1 Induces Neovascularization and Prevents Left Ventricular Remodeling in a Porcine Model of Ischemia Reperfusion.

Cytokine therapy has been suggested to improve left ventricle (LV) function after myocardial infarction (MI). The mechanisms for this benefit remain debatable. We investigated the impact of a prolonged combined therapy with Darbepoetin alfa (DARB) and Granulocyte Colony-Stimulating Factor (G-CSF) on LV function and vascular density after MI, correlating it with circulating progenitor cells (CPC), Vascular Endothelial Growth Factor (VEGF) and Stromal-Derived Factor 1 (SDF-1) release. Methods and Results : MI was induced in swine by a 90 minutes balloon occlusion of the left anterior descending artery. Animals were divided between treatment group with DARB-GCSF combination therapy (bolus of DARB 0.9 and GCSF 10ug/kg IV at time of reperfusion, followed by 5 doses of GCSF 5ug/kg SC from day 5 to 9, and four doses of 0.45ug/kg DARB SC once per week starting at day 1, n = 8) or control group (saline injections, n = 8). White blood cells (WBC), CPC, defined by CD45, CD31, CD90 and SLA-1 expression, and circulating levels of VEGF and SDF-1 were assessed at baseline (T0), 1 (T1), 2 (T2), and 3 (T3) weeks post-MI. LV function was assessed by echocardiography at T0, T1 and T6 (6 weeks post-MI), and vascular density by histology at T6. MI size was the same in both groups by post-MI CPK peak and LV ejection fraction (EF) at T1 (41+/−1 vs. 40+/−2%). In the treatment group only, from T0 to T1, there was an increase in WBC (16 ± 2 to 42 ± 2 x 10 6 /ml, p <0.01) and CPC (5 ± 1 to 9 ± 1 x 10 5 /ml, p = 0.01) and SDF-1 levels peaked from T0 to T2 (1345+/−60 to 1554 +/− 60 pg/ml; p<0.01) and stabilized at T3. All these values remained unchanged in the control group. VEGF levels (pg/ml) peaked at T2 in both groups (14+/−1 vs. 12+/−1), but remained increased at T3 in DARB-GCSF group only (13+/−1 vs. 9+/−1; p<0.01). LVEF (41+/−1 vs. 33+/−1, p<0.01) and arteriole density at the infarct zone (44+/−14 vs. 27+/−12/mm 2 , p = 0.02) and remote zone (18 +/−8 vs.11+/−5, p = 0.055) were higher compared to the control at T6. Conclusion : Our data suggest that prolonged therapy with DARB-GCSF combination after MI modulates angiogenesis and promotes stabilization of LV function by increasing CPC, and releasing SDF-1 and VEGF. This therapy provides a novel strategy to prevent post-MI LV remodeling and potentially improve outcome.

Mutations defining functional regions of the superantigen staphylococcal enterotoxin B.

Staphylococcal enterotoxin B (SEB) is both a superantigen and toxin. As a superantigen, SEB can bind to major histocompatibility complex (MHC) class II molecules to form a ligand for alpha/beta T cell receptors bearing particular V beta elements. As a toxin, SEB causes rapid weight loss in mice sometimes leading to death. We show here that both of these functions map to the NH2-terminal portion of the toxin. Three regions were identified: one important in MHC class II binding, one in T cell recognition, and one in both functions. These results support the conclusion that the toxicity of SEB is related to massive T cell stimulation and release of cytokine mediators and show that the residues interacting with MHC and the T cell receptor are intertwined.