TGF-β conditions intestinal T cells to express increased levels of miR-155, associated with down-regulation of IL-2 and itk mRNA.
Transforming growth factor (TGF)-β, is an immunosuppressive cytokine that inhibits T-cell activation. We hypothesized that TGF-β mediates its immunoinhibitory effects by modulation of micro RNA (miRNA)-155 (miR-155). Interleukin (IL)-2 and interferon-γ are down-regulated by TGF-β in activated CD4 peripheral blood T cells and lamina propria T cells (LPT), but miR-155 is upregulated ninefold specifically in LPT. Consequently, this study focuses on the role of TGF-β-enhanced miR-155 on LPT immune responses. TGF-β induces miR-155 in both freshly isolated and LPT lymphoblasts, whereas other inducible miRNAs are not regulated by TGF-β. Using MAMI bioinformatics database, we determined that inducible T-cell kinase (itk) is a functional target of miR-155 that exhibits an inverse mRNA response to that of miR-155. To determine experimentally that miR-155 regulates itk, transfection experiments were performed that demonstrated miR-155 overexpression decreased itk and IL-2 mRNA, whereas antagonism of miR-155 restored both mRNAs in activated cells. These findings describe a TGF-β-dependent function for miR-155 in modulating cytokine and T-cell immune responses in the gut.
Division of Gastroenterology and Liver Disease, Department of Medicine, Case Western Reserve University, Cleveland, Ohio, USA. lxd30@case.edu
L M
LM
Das
M D L A
MD
Torres-Castillo
T
T
Gill
A D
AD
Levine
D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D005786:Gene Expression Regulation / Q000187:drug effects; D020868:Gene Silencing; D006801:Humans; D007376:Interleukin-2 / Q000235:genetics*; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D035683:MicroRNAs / Q000235:genetics*; D011505:Protein-Tyrosine Kinases / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects* / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
D016207:Cytokines; D007376:Interleukin-2; C524942:MIRN155 microRNA, human; D035683:MicroRNAs; D012333:RNA, Messenger; D011948:Receptors, Antigen, T-Cell; D016212:Transforming Growth Factor beta; D011505:Protein-Tyrosine Kinases; C080813:emt protein-tyrosine kinase