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Séminaire

Vendredi 15 Septembre 2017
11h30
Centre de Recherche - Paris - Amphithéâtre Antoine Lacassagne

Identification of IL-40 and IL-41

My lab specializes in the identification and characterization of novel cytokines and chemokines. We have identified two novel cytokines that we have called IL-40 and IL-41. IL-40 is s small secreted protein encoded by an uncharacterized gene that is expressed by activated B cells. It is expressed in the bone marrow and fetal liver and it therefore is likely to be involved in B cell development. We have obtained an IL-40-/- mouse which exhibits defects in B cell development. In the periphery, IL-40 is expressed by activated B cells. Interestingly, B cells require differentiation in order to produce large amounts of IL-40. This involves culture with various cytokines including IL4 and TGFb. The IL-40-/- mouse exhibits defects in IgA production and in its gut microbiome.
IL-41 is a novel cytokine produced by activated macrophages. It is associated with inflammation and its expression by macrophages is regulated by several cytokines. Conversely, an IL-41-/- mouse exhibits dysregulation of cytokine production. We conclude from these observations that IL-41 is an immunoregulatory cytokine. Its expression is strongly induced during inflammatory responses and it is likely to play an important role in the control of inflammation.
We conclude that these are novel additions to the cytokine collection and that these molecules will prove to be important in both innate and acquired immunity.

 

Orateur(s)

Pr Albert Zlotnik
PhD, Associated Professor

Department of Physiology and Biophysics and Institute for Immunology, University of California Irvine. Irvine, CA, USA

Invité(e)(s) par

Vassili Soumelis
Domain 3 - U932 - Immunity and Cancer

Institut Curie

Contact

Vassili Soumelis

Institut Curie

Elodie Mieville

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One of the goals of my current research is to characterize a new cytokine encoded by a gene called C19ORF10, which we have observed that is expressed by certain activated T cells.

I have extensive experience in the discovery of cytokines and chemokines. I was part of the teams that first cloned and characterized IL4, IL-10, GM-CSF and FLT-3 Ligand; my own lab discovered and characterized many chemokines including CCL16, CCL19, CCL20, CCL21, CCL25, CCL27, CCL28, XCL1, CX3CL1, and CXCL15. We also found the chemokine receptors CCR7 and CCR10. Many of these cytokines and chemokines have become very famous and their importance in immunology has been well established. We have also studied the evolution of this superfamily. My laboratory also described a role for chemokines and their receptors in cancer metastasis. This paper opened a new field in chemokine research, and these results have been supported by clinical data. After leaving DNAX Research Institute in 2000, I worked at different biotechnology companies where I made extensive use of genearrays for analyses of many human diseases and tissues. This led to many patent applications (I am an inventor in 27 issued patents). Upon moving to the University of California in 2008 for my first academic position, I wanted to leverage my expertise in novel gene discovery as well as my extensive experience in cytokine and chemokine discovery to ask whether we could identify novel immune system associated genes (ISAGs). To find these genes, we analyzed a comprehensive database of human gene expression which we have described (Roth et al, Neurogenetics) which includes 105 tissues of the human body from 8 donors (4 male, 4 female). Using this database (called a “Body Index of Gene Expression: ‘BIGE’), we have identified 92 ISAGs that encode either secreted or membrane proteins.  In the past few years, my lab has described several novel ISAGs, including two secreted proteins: Isthmin 1 (ISM1), and Meteorin-like/Interleukin 41 (Metrnl/IL-41)(Ushach et al, Clin. Immunol).   as well as the novel B cell activation antigen Tetraspanin 33 (TSPAN33) and a novel chemokine receptor (GPR35/CXCR8). CXCR8 is the receptor of the mucosal chemokine CXCL17 which we have been characterizing. I have a proven record of successful and productive research in cytokine and chemokine biology. As we describe in our preliminary data, we have found that the CCL228/CCR10 axis is a very important player in mucosal immunity in particular resistance to Salmonella infection.

Ushach, I., A Burkhardt, C Martinez, PA Hevezi, A Gerber, B Buhren, H Schrump, R Vallerios, M Vazquez, B Homey and A Zlotnik. Meteorin-like is a cytokine associated with barrier tissues and alternatively activated macrophages. Clin Immunol. (2015) 1556:119.

Roth, RB, P Hevezi, J Lee, D Willhite, SM Lechner, SC Foster and A Zlotnik. Gene expression analyses reveal molecular relationships among 20 regions of the human CNS. (2006) Neurogenetics 7: 67.