Inductive microRNA‐21 impairs anti‐mycobacterial responses by targeting IL‐12 and Bcl‐2

miR‐21 has been shown to regulate multiple mRNAs and cause tumor progression and metastasis. However, whether miR‐21‐mediated posttranscriptional regulation is involved in antigen presentation and anti‐mycobacterial responses remains unclear. Here, we report that miR‐21 can be induced after Bacillus Calmette‐Guerin (BCG) vaccination by NF‐kB activation. miR‐21 suppressed IL‐12 production by targeting IL‐12p35, which impaired anti‐mycobacterial T cell responses both in vitro and in vivo. Additionally, miR‐21 also promoted dendritic cell (DC) apoptosis by targeting Bcl‐2. Therefore, miR‐21 may potentially be involved in fine‐tuning of the anti‐mycobacterial Th1 response and in regulating the efficacy of BCG vaccination.

[1]  WHO global tuberculosis control report 2010. Summary. , 2010, Central European journal of public health.

[2]  Shuomin Zhu,et al.  MicroRNA-21 targets tumor suppressor genes in invasion and metastasis , 2008, Cell Research.

[3]  P. Janson,et al.  MicroRNAs: Novel Regulators Involved in the Pathogenesis of Psoriasis? , 2007, PloS one.

[4]  M. Ernst,et al.  Defective antigen presentation by Mycobacterium tuberculosis-infected monocytes , 1994, Infection and immunity.

[5]  K. Floyd,et al.  Global burden and epidemiology of tuberculosis. , 2009, Clinics in chest medicine.

[6]  J. Ruland,et al.  Card9 controls a non-TLR signalling pathway for innate anti-fungal immunity , 2006, Nature.

[7]  A. Sher,et al.  TLR9 regulates Th1 responses and cooperates with TLR2 in mediating optimal resistance to Mycobacterium tuberculosis , 2005, The Journal of experimental medicine.

[8]  A. Schetter,et al.  MiR-21 is an EGFR-regulated anti-apoptotic factor in lung cancer in never-smokers , 2009, Proceedings of the National Academy of Sciences.

[9]  Andrea De Maria,et al.  Immunology of Tuberculosis , 2014, Mediterranean journal of hematology and infectious diseases.

[10]  A. Sher,et al.  Cutting Edge: Caspase-1 Independent IL-1β Production Is Critical for Host Resistance to Mycobacterium tuberculosis and Does Not Require TLR Signaling In Vivo , 2010, The Journal of Immunology.

[11]  B. Ryffel,et al.  IL-1 Receptor-Mediated Signal Is an Essential Component of MyD88-Dependent Innate Response to Mycobacterium tuberculosis Infection , 2007, The Journal of Immunology.

[12]  J. O’Shea,et al.  IFN-gamma production by antigen-presenting cells: mechanisms emerge. , 2001, Trends in immunology.

[13]  B. Li,et al.  IL-17-Producing Alveolar Macrophages Mediate Allergic Lung Inflammation Related to Asthma1 , 2008, The Journal of Immunology.

[14]  B. Hamasur,et al.  Immunization with heat-killed Mycobacterium bovis bacille Calmette-Guerin (BCG) in Eurocine L3 adjuvant protects against tuberculosis. , 2004, Vaccine.

[15]  H. Kornfeld,et al.  THP-1 Cell Apoptosis in Response to Mycobacterial Infection , 2003, Infection and Immunity.

[16]  T. Goldmann,et al.  Mycobacteria Induce IFN-γ Production in Human Dendritic Cells via Triggering of TLR21 , 2006, The Journal of Immunology.

[17]  A. Iwasaki,et al.  Toll-like receptor control of the adaptive immune responses , 2004, Nature Immunology.

[18]  A. Sher,et al.  Dectin-1 Interaction with Mycobacterium tuberculosis Leads to Enhanced IL-12p40 Production by Splenic Dendritic Cells1 , 2007, The Journal of Immunology.

[19]  S. Orkin,et al.  MicroRNA-21 Limits In Vivo Immune Response-Mediated Activation of the IL-12/IFN-γ Pathway, Th1 Polarization, and the Severity of Delayed-Type Hypersensitivity , 2011, The Journal of Immunology.

[20]  K. Kosik,et al.  MicroRNA-21 is an antiapoptotic factor in human glioblastoma cells. , 2005, Cancer research.

[21]  Y. Lau,et al.  Associations between IL12B polymorphisms and tuberculosis in the Hong Kong Chinese population. , 2004, The Journal of infectious diseases.

[22]  T. Goldmann,et al.  Mycobacteria induce IFN-gamma production in human dendritic cells via triggering of TLR2. , 2006, Journal of immunology.

[23]  I. Humphreys,et al.  A role for dendritic cells in the dissemination of mycobacterial infection. , 2006, Microbes and infection.

[24]  M. Chambers,et al.  A single dose of killed Mycobacterium bovis BCG in a novel class of adjuvant (Novasome) protects guinea pigs from lethal tuberculosis. , 2004, Vaccine.

[25]  C. Czuprynski.  Faculty Opinions recommendation of Mycobacterium tuberculosis infects dendritic cells with high frequency and impairs their function in vivo. , 2007 .

[26]  Shuomin Zhu,et al.  MicroRNA-21 Targets the Tumor Suppressor Gene Tropomyosin 1 (TPM1)* , 2007, Journal of Biological Chemistry.

[27]  C. Dye.  Global epidemiology of tuberculosis , 2006, The Lancet.

[28]  Marc E. Rothenberg,et al.  MicroRNA-21 Is Up-Regulated in Allergic Airway Inflammation and Regulates IL-12p35 Expression 1 , 2009, The Journal of Immunology.

[29]  A. O’Garra,et al.  The role of IL-10 in immune regulation during M. tuberculosis infection , 2011, Mucosal Immunology.

[30]  Ryan M. O’Connell,et al.  Physiological and pathological roles for microRNAs in the immune system , 2010, Nature Reviews Immunology.

[31]  S. Hickman,et al.  Disparity in IL-12 Release in Dendritic Cells and Macrophages in Response to Mycobacterium tuberculosis Is Due to Use of Distinct TLRs1 , 2007, The Journal of Immunology.

[32]  A. Krogh,et al.  Programmed Cell Death 4 (PDCD4) Is an Important Functional Target of the MicroRNA miR-21 in Breast Cancer Cells* , 2008, Journal of Biological Chemistry.

[33]  T. Hawn,et al.  Mycobacterium tuberculosis, macrophages, and the innate immune response: does common variation matter? , 2007, Immunological reviews.

[34]  A. Sher,et al.  Role of innate cytokines in mycobacterial infection , 2011, Mucosal Immunology.

[35]  S. Koyasu,et al.  In vivo role of IFN‐γ produced by antigen‐presenting cells in early host defense against intracellular pathogens , 2003, European journal of immunology.

[36]  E. Pålsson-McDermott,et al.  Negative regulation of TLR4 via targeting of the proinflammatory tumor suppressor PDCD4 by the microRNA miR-21 , 2010, Nature Immunology.

[37]  Xuan Pan,et al.  MicroRNA-21: A novel therapeutic target in human cancer , 2010, Cancer biology & therapy.

[38]  J. Ernst,et al.  Initiation of the adaptive immune response to Mycobacterium tuberculosis depends on antigen production in the local lymph node, not the lungs , 2008, The Journal of experimental medicine.

[39]  C. Harding,et al.  Regulation of antigen presentation by Mycobacterium tuberculosis: a role for Toll-like receptors , 2010, Nature Reviews Microbiology.

[40]  S. Swain,et al.  Interleukin 12p40 is required for dendritic cell migration and T cell priming after Mycobacterium tuberculosis infection , 2006, The Journal of experimental medicine.

[41]  Shigeo Koyasu,et al.  IFN-γ production by antigen-presenting cells: mechanisms emerge , 2001 .

[42]  Shuomin Zhu,et al.  miR-21-mediated tumor growth , 2007, Oncogene.

[43]  I. Orme,et al.  Interleukin 12 (IL-12) Is Crucial to the Development of Protective Immunity in Mice Intravenously Infected with Mycobacterium tuberculosis , 1997, The Journal of experimental medicine.

[44]  W. Rom,et al.  Copyright © 1997, American Society for Microbiology Effects of Mycobacteria on Regulation of Apoptosis in , 1997 .

[45]  H. Horvitz,et al.  MicroRNA expression profiles classify human cancers , 2005, Nature.

[46]  K. Ghoshal,et al.  MicroRNA-21 regulates expression of the PTEN tumor suppressor gene in human hepatocellular cancer. , 2007, Gastroenterology.

[47]  F. Brombacher,et al.  A Protective and Agonistic Function of IL-12p40 in Mycobacterial Infection1 , 2001, The Journal of Immunology.

[48]  D. Baltimore,et al.  MicroRNAs and immunity: tiny players in a big field. , 2007, Immunity.

[49]  C. Klinge,et al.  Estradiol downregulates miR-21 expression and increases miR-21 target gene expression in MCF-7 breast cancer cells , 2009, Nucleic acids research.

[50]  D. Underhill,et al.  Faculty Opinions recommendation of Caspase-1 independent IL-1beta production is critical for host resistance to mycobacterium tuberculosis and does not require TLR signaling in vivo. , 2010 .

[51]  Christopher Dye,et al.  The growing burden of tuberculosis: global trends and interactions with the HIV epidemic. , 2003, Archives of internal medicine.

[52]  A. Cooper,et al.  Cell-mediated immune responses in tuberculosis. , 2009, Annual review of immunology.

[53]  D. Bartel.  MicroRNAs Genomics, Biogenesis, Mechanism, and Function , 2004, Cell.