Institute for Genetic Immunology

Hamilton Square, NJ, United States

Institute for Genetic Immunology

Hamilton Square, NJ, United States
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Yu R.Y.,Institute for Genetic Immunology | Gallagher G.,Institute for Genetic Immunology
Journal of Immunology | Year: 2010

Th17 CD4 cells are critical to inflammation. Their secretion of IL-17 drives inflammation in human diseases, including inflammatory bowel disease. Differentiation of mature Th17 cells depends on stimulation with IL-6, TGF-β, and IL-21 and the induction of RORγt, but IL-23 is essential to Th17 phenotype, stability, and function. Induction of Th17 cells can be antagonized by IL-4 or IFN-γ, but mechanisms through which terminal differentiation can be inhibited have not been identified. Human IL-23Ra (HuIL23Rα)-chain mRNA transcripts exist that lack exon 9 ("Δ9"); these are translated to a truncated receptor containing the entire external domain. This soluble variant of the HuIL23Rα-chain antagonizes Th17 maturation. It is secreted and present at low levels in the blood. It represents 10% of HuIL23Rα-chain mRNA, binds IL-23 in solution, and inhibits the phosphorylation of STAT3 caused by IL-23. In in vitro Th17 cell differentiation experiments, D9 inhibits the production of the Th17-associated cytokines IL-17A and IL-17F. Δ9 does not bind IL-12; thus, it is a specific inhibitor of IL-23 and a modulator of Th17 cells. Our results indicate that this soluble form of HuIL23Ra likely functions to regulate Th17 activity. Copyright © 2010 by The American Association of Immunologists, Inc.


Siegel R.,Institute for Genetic Immunology | Eskdale J.,Institute for Genetic Immunology | Gallagher G.,Institute for Genetic Immunology
Journal of Immunology | Year: 2011

The type III (λ) IFNs (IFN-λ1, IFN-λ2, and IFN-λ3) and their receptor are the most recently discovered IFN family. They are induced by viruses and mediate antiviral activity, but type III IFNs have an important, specific functional niche at the immune/ epithelial interface, as well as in the regulation of Th2 cytokines. Their expression appears diminished in bronchial epithelial cells of rhinovirus-infected asthmatic individuals. We investigated the regulation of IFN-λ1 expression in human airway epithelial cells using reporter genes analysis, chromatin immunoprecipitation, small interfering RNA knockdown, and DNase footprinting. In this article, we define the c-REL/p65 NF-κB heterodimer and IRF-1 as key transcriptional activators and ZEB1, B lymphocyte-induced maturation protein 1, and the p50 NF-κB homodimer as key repressors of the IFN-λ1 gene. We further show that ZEB1 selectively regulates type III IFNs. To our knowledge, this study presents the first characterization of any type III IFN promoter in its native context and conformation in epithelial cells and can now be applied to understanding pathogenic dysregulation of IFN-λ1 in human disease. Copyright © 2011 by The American Association of Immunologists, Inc.


Gallagher G.,Institute for Genetic Immunology
Cytokine and Growth Factor Reviews | Year: 2010

First reported in 1999, IL-19 remains a mystery in many ways. Despite appearing in many genome scans and candidate gene studies, and having been searched for specifically as part of the IL-10 family, its function is still to be defined. Nonetheless, a pattern of Th2 promotion is coalescing from this nebulous body of work, supported by increasing evidence for a role in asthma. Similarly, a clear but less intuitive role as a subtle immunomodulator is emerging in psoriasis and chronic inflammatory disorders in general. Indeed, several human diseases and their animal models have highlighted a role for IL-19. Key questions remain, relating to the nature of its receptor, its function (if any) on leukocytes and how its effects are distinguished by the cell from those of IL-20 and IL-24. In this review, I shall attempt to bring together a summary of the known work - disparate as it may be - as well as presenting a picture of these two important clinical disorders and the potential involvement of this somewhat enigmatic cytokine. © 2010 Elsevier Ltd.

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