LFA-1/ICAM-1 Ligation in Human T Cells Promotes Th1 Polarization through a GSK3β Signaling–Dependent Notch Pathway

Verma, Navin Kumar; Fazil, Mobashar Hussain Urf Turabe; Ong, Seow Theng; Chalasani, Madhavi Latha Somaraju; Low, Jian Hui; Kottaiswamy, Amuthavalli; P, Praseetha; Kizhakeyil, Atish; Kumar, Sunil; Panda, Aditya K.; Freeley, Michael; Smith, Sinead; Boehm, Bernhard O.; Kelleher, Dermot

doi:10.4049/jimmunol.1501264

Cited by 54 publications

(59 citation statements)

References 40 publications

(52 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Migration is dependent on interactions between LFA-1 and ICAM-1. 45,46 Del-1, as an antagonist of LFA-1, interferes with LFA-1-ICAM-1 interactions and inhibits the expression of ICAM-1. 15 In addition, IL-17 can improve ICAM-1 expression to enhance inflammation.…”

Section: Discussionmentioning

confidence: 99%

Developmental endothelial locus‐1 (Del‐1) antagonizes Interleukin‐17‐mediated allergic asthma

et al. 2018

View full text Add to dashboard Cite

Interleukin (IL)-17 is a major contributor to the pathogenesis of allergic asthma. Developmental endothelial locus-1 (Del-1) is an endothelial cell-secreted protein known to inhibit IL-17 expression. However, little is known about the association between Del-1 and IL-17 in the pathogenesis of allergic asthma. Using bronchoalveolar lavage fluid (BALF) and peripheral blood samples collected from allergic asthmatic patients and controls, we explored the role of Del-1 in relation to IL-17 in allergic asthma. We found that the negative correlation between Del-1 and IL-17 was significant in BALF of allergic asthmatics. Del-1 treatment inhibited the expression of IL-17, the differentiation of IL-17-secreting leukocytes and associated cytokines. Contrarily, IL-17 levels were increased after treatment with anti-Del-1 mAb. Consistent with this, Del-1 treatment led to downregulation of IL-5, CCL5 and IL-4, thus reducing secretion of eosinophil cationic protein. Furthermore, Del-1 significantly downregulated the expression of ICAM-1 and may have the potential to reduce leukocyte transendothelial migration. Our data demonstrate that Del-1 can negatively regulate IL-17 and its proinflammatory function, thereby limiting airway inflammation in allergic asthmatics, and suggest Del-1 as a potential candidate for prevention and treatment of allergic asthma.

show abstract

Section: Discussionmentioning

confidence: 99%

Developmental endothelial locus‐1 (Del‐1) antagonizes Interleukin‐17‐mediated allergic asthma

et al. 2018

View full text Add to dashboard Cite

show abstract

“…This hypothesis is in fact supported by a recent study demonstrating that ICAM1-LFA1 signaling in T cells promotes a Th1-dominant response. 50 Further studies are ongoing to define the downstream mechanism by which decreased expression of RNASET2 modulates cytokine secretion in the context of IBD pathogenesis.…”

Section: Discussionmentioning

confidence: 99%

Association of Ribonuclease T2 Gene Polymorphisms With Decreased Expression and Clinical Characteristics of Severity in Crohn’s Disease

et al. 2017

View full text Add to dashboard Cite

Background & Aims Variants in the tumor necrosis factor superfamily member 15 gene (TNFSF15, also called TL1A) have been associated with risk for inflammatory bowel diseases (IBD). TL1A affects expression of multiple cytokines to promote mucosal inflammation. Little is known about the TL1A-response pathways that regulate cytokine expression. We investigated T-cell gene expression patterns to determine the mechanisms by which TL1A regulates cytokine production, and whether these associate with outcomes of patients with Crohn’s disease (CD). Methods Peripheral T cells isolated from normal donors were cultured with TL1A. We performed gene expression profile analysis, by RNA sequencing, of subsets of interferon gamma (IFNG)-producing and non-producing cells, purified by flow cytometry. Unsupervised hierarchical clustering analysis was used to identify gene expression differences between these subsets. Ribonuclease T2 gene (RNASET2) expression and methylation were assessed by quantitative trait loci analyses. Clinical characteristics of patients (complications, resistance to therapy, recurrence time) were associated with single nucleotide polymorphisms in RNASET2. We performed motif screening to identify polymorphisms that disrupt transcription factor binding sites. Levels of RNASET2 were knocked down with small interfering RNA in CD4+ T cells and the effect on protein expression was determined by proteomic analysis and cytokine production. Cell aggregation was measured by flow cytometry. Results We identified 764 genes with at least a 2-fold difference in TL1A-mediated expression between IFNG-secreting and non-secreting T cells (P<1 × 10−5). Many of these genes were located near IBD susceptibility variants. RNASET2 was the only IBD risk-associated gene with greater than 5-fold downregulation in the IFNG-secreting subset. RNASET2 disease risk variants were associated with decreased expression in peripheral and mucosal tissues and DNA hypermethylation in CD patients requiring surgical intervention. RNASET2 disease risk variants were associated in CD patients with more complicated disease or resistance to therapy, defined in part by failed response to treatment, increased length of intestinal resection, shorter time to repeat surgery, and high Rutgeerts score (>2) in post-operative endoscopy. The RNASET2 variant rs2149092 was predicted to disrupt a consensus binding site for the transcription factor ETS within an enhancer region. Expression of RNASET2 correlated with expression of ETS. RNASET2 knockdown in T cells increased expression of IFNG and ICAM1 and induced T cells aggregation. A blocking antibody against LFA1, disrupting the LFA1-ICAM1 interaction, reduced T-cell production of IFNG. Conclusions We identified decreased expression of RNASET2 as a component of TL1A-mediated increase in production of IFNG and as a potential biomarker for patients with severe CD. Further study of the role of RNASET2 in regulating mucosal inflammation may lead to development of novel therapeutic targets.

show abstract

“…The costimulatory signal of T-cell activation process emanates from adhesion effects between the costimulatory signal of T-cell and ligand of antigenpresenting cells. ICAM-1/LFA-1 is one of them [19]. VCAM-1 is located on the surface of various cells.…”

Section: Discussionmentioning

confidence: 99%

Leucine zipper transcription factor-like 1 expression in gastric cancer and its relationship to relative adhesion molecule

Lian¹,

Li²,

Hui-fen³

et al. 2017

Trop. J. Pharm Res

View full text Add to dashboard Cite

LFA-1/ICAM-1 Ligation in Human T Cells Promotes Th1 Polarization through a GSK3β Signaling–Dependent Notch Pathway

Cited by 54 publications

References 40 publications

Developmental endothelial locus‐1 (Del‐1) antagonizes Interleukin‐17‐mediated allergic asthma

Developmental endothelial locus‐1 (Del‐1) antagonizes Interleukin‐17‐mediated allergic asthma

Association of Ribonuclease T2 Gene Polymorphisms With Decreased Expression and Clinical Characteristics of Severity in Crohn’s Disease

Leucine zipper transcription factor-like 1 expression in gastric cancer and its relationship to relative adhesion molecule

Contact Info

Product

Resources

About