title: CD5 promotes IL-10 production in chronic lymphocytic leukemia B cells through STAT3 and NFAT2 activation.
abstract: B lymphocytes from chronic lymphocytic leukemia (CLL) display some CD5 transcripts for CD5 containing the known exon 1 (E1A) and other CD5 transcripts containing the new exon 1 (E1B). These malignant B cells, as well as B cell lines transfected with cDNA for E1A-cd5 or with cDNA for E1B-cd5 produce IL-10, raising the possibility that CD5 participates in the secretion of IL-10. We identified transcription factors involved in this production in CD5(+) B lymphocytes from CLL patients and in E1A-cd5-transfected or E1B-cd5-transfected Jok cells. STAT3 is activated via phosphorylation of serine 727 but also NFAT2 through its translocation into the nucleus. Chromatin immunoprecipitation experiments confirmed the role of STAT3 and allowed the discovery of a role for NFAT2 in IL-10 production. Both transcription factors bind not only to the enhancer of the Il-10 gene but also to the promoter of the Il-5 and Il-13 genes. Furthermore, transfection of B cell lines with E1A-cd5 or E1B-cd5 established that activation of STAT3 and NFAT2 is regulated by CD5. The same holds true for the production of IL-10, IL-5, and IL-13 and the expression of the receptors for these cytokines. This interpretation was confirmed by two experiments. In the first, downregulation of CD5 by small interfering RNAs lowered the production of IL-10. In the second experiment, transfection of the GFP-NFAT2 gene into B lymphocytes induced nuclear translocation of NFAT2 in CD5(+) but not in CD5(-) B cells. Thus, CD5 expression is associated with NFAT2 activity (and mildly STAT3 activity), indicating that CD5 controls IL-10 secretion.
authors.affiliation: EA2216 Immunology and Pathology, IFR 148 ScInBioS, European University of Brittany, F29609 Brest, France.
authors.forename: Soizic
authors.initials: S
authors.lastname: Garaud
authors.forename: Ahsen
authors.initials: A
authors.lastname: Morva
authors.forename: Sébastien
authors.initials: S
authors.lastname: Lemoine
authors.forename: Sophie
authors.initials: S
authors.lastname: Hillion
authors.forename: Anne
authors.initials: A
authors.lastname: Bordron
authors.forename: Jacques-Olivier
authors.initials: JO
authors.lastname: Pers
authors.forename: Christian
authors.initials: C
authors.lastname: Berthou
authors.forename: Rizgar A
authors.initials: RA
authors.lastname: Mageed
authors.forename: Yves
authors.initials: Y
authors.lastname: Renaudineau
authors.forename: Pierre
authors.initials: P
authors.lastname: Youinou
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D001402:B-Lymphocytes / Q000378:metabolism*; D015153:Blotting, Western; D018956:CD5 Antigens / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D002648:Child; D005260:Female; D015870:Gene Expression; D056945:Hep G2 Cells; D006801:Humans; D007231:Infant, Newborn; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism*; D018793:Interleukin-13 / Q000235:genetics / Q000378:metabolism; D015848:Interleukin-5 / Q000235:genetics / Q000378:metabolism; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D012694:Serine / Q000378:metabolism
chemical_list: D018956:CD5 Antigens; D018793:Interleukin-13; D015848:Interleukin-5; D050778:NFATC Transcription Factors; D050796:STAT3 Transcription Factor; D016753:Interleukin-10; D012694:Serine