title: IL-1β promotes antimicrobial immunity in macrophages by regulating TNFR signaling and caspase-3 activation.
abstract: In vivo control of Mycobacterium tuberculosis reflects the balance between host immunity and bacterial evasion strategies. Effector Th1 cells that mediate protective immunity by depriving the bacterium of its intracellular niche are regulated to prevent overexuberant inflammation. One key immunoregulatory molecule is Tim3. Although Tim3 is generally recognized to downregulate Th1 responses, we recently described that its interaction with Galectin-9 expressed by M. tuberculosis-infected macrophages stimulates IL-1β secretion, which is essential for survival in the mouse model. Why IL-1β is required for host resistance to M. tuberculosis infection is unknown. In this article, we show that IL-1β directly kills M. tuberculosis in murine and human macrophages and does so through the recruitment of other antimicrobial effector molecules. IL-1β directly augments TNF signaling in macrophages through the upregulation of TNF secretion and TNFR1 cell surface expression, and results in activation of caspase-3. Thus, IL-1β and downstream TNF production lead to caspase-dependent restriction of intracellular M. tuberculosis growth.
authors.affiliation: Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA. pushpa.jayaraman@umassmed.edu
authors.forename: Pushpa
authors.initials: P
authors.lastname: Jayaraman
authors.forename: Isabel
authors.initials: I
authors.lastname: Sada-Ovalle
authors.forename: Tomoyasu
authors.initials: T
authors.lastname: Nishimura
authors.forename: Ana C
authors.initials: AC
authors.lastname: Anderson
authors.forename: Vijay K
authors.initials: VK
authors.lastname: Kuchroo
authors.forename: Heinz G
authors.initials: HG
authors.lastname: Remold
authors.forename: Samuel M
authors.initials: SM
authors.lastname: Behar
mesh_terms: D000818:Animals; D053148:Caspase 3 / Q000378:metabolism*; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000276:immunology; D006801:Humans; D053583:Interleukin-1beta / Q000502:physiology*; D008264:Macrophages / Q000201:enzymology / Q000276:immunology* / Q000382:microbiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009169:Mycobacterium tuberculosis / Q000276:immunology; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism* / Q000502:physiology; D015398:Signal Transduction / Q000276:immunology*; D015854:Up-Regulation / Q000276:immunology
chemical_list: D053583:Interleukin-1beta; D018124:Receptors, Tumor Necrosis Factor; D053148:Caspase 3