title: Human Invariant NKT Cells Induce IL-1β Secretion by Peripheral Blood Monocytes via a P2X7-Independent Pathway.
abstract: The cytokine IL-1β plays a central role in inflammatory responses that are initiated by microbial challenges, as well as in those that are due to endogenous processes (often called sterile inflammation). IL-1β secretion that occurs independently of microbial stimulation is typically associated with the presence of endogenous alarmins, such as extracellular ATP (an indicator of cytopathic damage). In this study, we show that IL-2-activated human invariant NKT (iNKT) cells stimulate the secretion of IL-1β protein by human peripheral blood monocytes in a manner that requires neither the presence of microbial compounds nor signaling through the extracellular ATP receptor P2X7 Monocyte IL-1β production was specifically induced by iNKT cells, because similarly activated polyclonal autologous T cells did not have this effect. Secretion of IL-1β protein occurred rapidly (within 3-4 h) and required cell contact between the iNKT cells and monocytes. Similar to IL-1β production induced by TLR stimulation, the iNKT-induced pathway appeared to entail a two-step process involving NF-κB signaling and IL1B gene transcription, as well as assembly of the NLRP3 inflammasome and activation of caspase-1. However, in contrast to the classical inflammasome-mediated pathway of IL-1β production, activation of monocytes via P2X7 was dispensable for iNKT-induced IL-1β secretion, and potassium efflux was not required. Moreover, the iNKT-induced effect involved caspase-8 activity, yet it induced little monocyte death. These results suggest that IL-2-activated human iNKT cells induce monocytes to produce IL-1β through a distinctive pathway that does not require the presence of microbial danger signals or alarmins associated with cytopathic damage.
authors.affiliation: Department of Medical Microbiology and Immunology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53706; and.
authors.forename: Laura E
authors.initials: LE
authors.lastname: Felley
authors.affiliation: Department of Medical Microbiology and Immunology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53706; and.
authors.forename: Akshat
authors.identifier: 0000-0002-2632-2935
authors.initials: A
authors.lastname: Sharma
authors.affiliation: Department of Medical Microbiology and Immunology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53706; and.
authors.forename: Erin
authors.initials: E
authors.lastname: Theisen
authors.affiliation: Department of Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53706.
authors.forename: James C
authors.initials: JC
authors.lastname: Romero-Masters
authors.affiliation: Department of Medical Microbiology and Immunology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53706; and.
authors.forename: John-Demian
authors.identifier: 0000-0001-9367-794X
authors.initials: JD
authors.lastname: Sauer
authors.affiliation: Department of Medical Microbiology and Immunology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53706; and jegumperz@wisc.edu.
authors.forename: Jenny E
authors.initials: JE
authors.lastname: Gumperz
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000067531:Alarmins / Q000276:immunology; D020170:Caspase 1 / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D006801:Humans; D058847:Inflammasomes; D053583:Interleukin-1beta / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D007376:Interleukin-2 / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D009000:Monocytes / Q000276:immunology*; D016328:NF-kappa B / Q000378:metabolism; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000276:immunology / Q000502:physiology; D055611:Natural Killer T-Cells / Q000187:drug effects / Q000276:immunology*; D058486:Receptors, Purinergic P2X7 / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D000067531:Alarmins; D016207:Cytokines; D058847:Inflammasomes; D053583:Interleukin-1beta; D007376:Interleukin-2; D008070:Lipopolysaccharides; D016328:NF-kappa B; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; C546468:P2RX7 protein, human; D058486:Receptors, Purinergic P2X7; D000255:Adenosine Triphosphate; D020170:Caspase 1