title: IL-27 inhibits IFN-γ induced autophagy by concomitant induction of JAK/PI3 K/Akt/mTOR cascade and up-regulation of Mcl-1 in Mycobacterium tuberculosis H37Rv infected macrophages.
abstract: Interleukin-27 (IL-27), a key immunoregulatory cytokine plays an important role in host response to mycobacterial infection as neutralization of IL-27 augments intracellular killing of mycobacteria. Autophagy has a pivotal role in host immunity and is regulated by various cytokines. Here, we report that IL-27 inhibits IFN-γ and starvation induced autophagy and as a result blocks phagosome maturation and promotes intracellular survival of Mycobacterium tuberculosis H37Rv. Addition of exogenous IL-27 induces the activation of mTOR through JAK/PI3 K pathway and inhibits IFN-γ stimulated autophagy. Furthermore, blockade of JAKs obstructs the inhibitory effect of IL-27 on IFN-γ induced autophagy. Besides this, IL-27 also up-regulates Mcl-1 through PI3 K pathway. We further show that in mTOR or Mcl-1 silenced THP-1 cells, IL-27 could no longer inhibit IFN-γ mediated autophagy in M. tuberculosis H37Rv infected cells. Altogether, our study demonstrates that IL-27 by concurrent activation of JAK/PI3 K/Akt/mTOR cascade as well as up-regulation of Mcl-1 inhibits IFN-γ induced autophagy and elimination of intracellular mycobacteria in macrophages.
authors.affiliation: Division of Cell Biology and Immunology, Institute of Microbial Technology (CSIR), Chandigarh 160036, India.
authors.forename: Gaurav
authors.initials: G
authors.lastname: Sharma
authors.affiliation: Division of Cell Biology and Immunology, Institute of Microbial Technology (CSIR), Chandigarh 160036, India.
authors.forename: Rajesh Kumar
authors.initials: RK
authors.lastname: Dutta
authors.affiliation: Division of Cell Biology and Immunology, Institute of Microbial Technology (CSIR), Chandigarh 160036, India.
authors.forename: Mohammad Aslam
authors.initials: MA
authors.lastname: Khan
authors.affiliation: Division of Cell Biology and Immunology, Institute of Microbial Technology (CSIR), Chandigarh 160036, India.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Ishaq
authors.affiliation: Division of Cell Biology and Immunology, Institute of Microbial Technology (CSIR), Chandigarh 160036, India.
authors.forename: Kapil
authors.initials: K
authors.lastname: Sharma
authors.affiliation: Division of Cell Biology and Immunology, Institute of Microbial Technology (CSIR), Chandigarh 160036, India.
authors.forename: Himanshu
authors.initials: H
authors.lastname: Malhotra
authors.affiliation: Division of Cell Biology and Immunology, Institute of Microbial Technology (CSIR), Chandigarh 160036, India. Electronic address: majumdar@imtech.res.in.
authors.forename: Sekhar
authors.initials: S
authors.lastname: Majumdar
mesh_terms: D001343:Autophagy / Q000187:drug effects* / Q000235:genetics; D045744:Cell Line, Tumor; D054884:Host-Pathogen Interactions; D006801:Humans; D015151:Immunoblotting; D007371:Interferon-gamma / Q000494:pharmacology*; D064094:Interleukin-27 / Q000494:pharmacology*; D053612:Janus Kinases / Q000235:genetics / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism / Q000382:microbiology; D018613:Microscopy, Confocal; D046529:Microscopy, Electron, Transmission; D009169:Mycobacterium tuberculosis / Q000502:physiology; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000235:genetics / Q000378:metabolism*; D010588:Phagosomes / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D010770:Phosphotransferases / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D007371:Interferon-gamma; D064094:Interleukin-27; D053612:Janus Kinases; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019869:Phosphatidylinositol 3-Kinases; D010770:Phosphotransferases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; C579095:MCL1 protein, human
keywords: Autophagy; IFN-γ; IL-27; Mycobacteria