Dysregulation of JAK/STAT genes by vasoactive intestinal peptide (VIP) in Salmonella-infected monocytes may inhibit its therapeutic potential in human sepsis
CYTOKINE
Authors: Ibrahim, Hiba; Askar, Basim; Barrow, Paul; Foster, Neil
Abstract
Murine/LPS models of Gram negative sepsis indicate that vasoactive intestinal peptide (VIP) has therapeutic potential. We investigated the unknown effect of VIP on JAK/STAT proteins and genes in human monocytes infected with Salmonella Typhimurium 14028. S. Typhimurium 14028 increased expression of both IL-6 receptor (IL-6R) and interferon gamma receptor 1 (IFN gamma R1) on monocytes but co-culture of infected monocytes with VIP (10(-7) M) only decreased expression of IFN gamma R1 (P < 0.05). In contrast, S. Typhimurium 14028 infection or co-culture with VIP had no effect on IL-10 receptor expression on the monocyte surface. However, S. Typhimurium 14028 down regulated IFNGR1 gene expression and this was not altered by co-culture with VIP, suggesting that changes in IFN gamma R1 protein may be due to an effect on cytoplasmic transport. 15 JAK/STAT genes, out of 84 studied, were up-regulated by S. Typhimurium 14028 infection and five were down-regulated. Co-culture with VIP significantly decreased expression of two genes (IFNG and IL-20) and increased expression of three genes (SOCS1, SOCS3 and STAT4) (P < 0.05). S. Typhimurium 14028 also increased expression of PTPN1, which dephosphorylates JAK2 and TYK2. This was unaltered by co-culture with VIP but S. Typhimurium 14028-induced expression of ISG15, associated with susceptibility to Gram negative infection, was further increased by VIP. We conclude that the effect of VIP on JAK/STAT genes may preclude its therapeutic use in human Gram negative sepsis.
Association of Single Nucleotide Polymorphisms in TNFA and IL10 Genes with Disease Severity in Influenza A/H1N1pdm09 Virus Infections: A Study from Western India
VIRAL IMMUNOLOGY
Authors: Choudhary, Manohar Lal; Alagarasu, Kalichamy; Choudhary, Urmila; Kawale, Samruddhi; Malasane, Prachi; Gurav, Yogesh K.; Padbidri, Vikram; Kadam, Deelip; Sangle, Shashikala A.; Salvi, Sonali; Bavdekar, Ashish R.; D'costa, Pradeep; Chadha, Mandeep S.
Abstract
Susceptibility to severe influenza A/H1N1pdm09 virus is multifactorial. The present study was carried out in 246 patients infected with A/H1N1pdm09 virus to find out whether single nucleotide polymorphisms (SNPs) in the genes coding for proinflammatory and anti-inflammatory cytokines are associated with disease severity. Among the cases, 129 had mild disease, whereas 117 had severe disease. There were 27 fatal cases. TNFA rs1800629, IFNG rs2430561, IL10 rs1800872, IL10 rs1800896, and CCL2 rs1024611 SNPs were genotyped by polymerase chain reaction-based methods. A significantly higher frequency of TNFA rs1800629 "G/A" genotype was observed in severe and fatal cases compared with mild and survived cases, respectively. In a dominant mode, IL10 rs1800896 "G" allele was significantly negatively associated with disease severity. IL10 rs1800896 "C/A" genotype was significantly associated with fatality in influenza A/H1N1pdm09 infections. The results suggest that SNPs in the IL10 and TNFA genes might be associated with disease severity in influenza A/H1N1pdm09-infected patients.