title: Monocytes and dendritic cells are the primary sources of interleukin 37 in human immune cells.
abstract: The interleukin (IL)-1 family member IL-37 is one of few anti-inflammatory cytokines, and it is capable of countering a broad spectrum of proinflammatory assaults. Although it is known that leukocytes are a major source of IL-37, knowledge on IL-37 production and secretion in specific immune cell types remains limited. Thus, we investigated IL-37 mRNA expression as well as protein production and secretion in human PBMCs. In PBMCs stimulated with agonists of Toll-like receptors (TLRs) 1-6 and 9,IL1F7(the IL-37-encoding gene) was induced up to 9-fold, peaked at 6-8 h and returned to steady-state at 72 h. LPS-inducedIL1F7expression comprised isoformsbandcbut notaandeFlow cytometry revealed that among IL-37+PBMCs, monocytes predominated (81-91%), but T cells (6-8%) and myeloid dendritic cells (mDCs, 1-2%) also contributed to the IL-37+leukocyte pool. Monocytes and mDCs, but not T cells, were capable of secreting IL-37. Whereas monocytes and mDCs secreted IL-37 upon LPS stimulation, only mDCs also released IL-37 at steady-state. Among monocyte subsets, IL-37 was LPS inducible and secreted only in classical and, although less pronounced, in intermediate monocytes; secretion was observed as early as 3 h after stimulation. Overall, our data suggest that constitutive IL-37 secretion by mDCs may serve to maintain an anti-inflammatory milieu at steady state, whereas IL-37 is stored in monocytes to be available for rapid release upon inflammatory encounters, thus acting as a novel anti-inflammatory alarmin. These insights may prove important to advancing towards clinical use the protective functions of one of the most powerful anti-inflammatory mediators so far discovered.
authors.affiliation: Ritchie Centre, Hudson Institute of Medical Research, Melbourne, Victoria, Australia.|Department of Paediatrics, Monash University, Melbourne, Victoria, Australia.
authors.forename: Ina
authors.initials: I
authors.lastname: Rudloff
authors.affiliation: Ritchie Centre, Hudson Institute of Medical Research, Melbourne, Victoria, Australia.|Department of Paediatrics, Monash University, Melbourne, Victoria, Australia.
authors.forename: Steven X
authors.initials: SX
authors.lastname: Cho
authors.affiliation: Ritchie Centre, Hudson Institute of Medical Research, Melbourne, Victoria, Australia.|Department of Paediatrics, Monash University, Melbourne, Victoria, Australia.
authors.forename: Jason C
authors.initials: JC
authors.lastname: Lao
authors.affiliation: Ritchie Centre, Hudson Institute of Medical Research, Melbourne, Victoria, Australia.|Department of Paediatrics, Monash University, Melbourne, Victoria, Australia.
authors.forename: Devi
authors.initials: D
authors.lastname: Ngo
authors.affiliation: Centre for Genetic Diseases, Hudson Institute of Medical Research, Melbourne, Victoria, Australia; and.|Department of Molecular and Translational Science, Monash University, Melbourne, Victoria, Australia.
authors.forename: Matthew
authors.initials: M
authors.lastname: McKenzie
authors.affiliation: Ritchie Centre, Hudson Institute of Medical Research, Melbourne, Victoria, Australia.|Department of Paediatrics, Monash University, Melbourne, Victoria, Australia.
authors.forename: Claudia A
authors.initials: CA
authors.lastname: Nold-Petry
authors.affiliation: Ritchie Centre, Hudson Institute of Medical Research, Melbourne, Victoria, Australia; marcel.nold@monash.edu.|Department of Paediatrics, Monash University, Melbourne, Victoria, Australia.
authors.forename: Marcel F
authors.initials: MF
authors.lastname: Nold
mesh_terms: D000328:Adult; D003713:Dendritic Cells / Q000187:drug effects / Q000378:metabolism*; D005434:Flow Cytometry; D006801:Humans; D007375:Interleukin-1 / Q000378:metabolism*; D007700:Kinetics; D008024:Ligands; D008070:Lipopolysaccharides / Q000494:pharmacology; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism*; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D051193:Toll-Like Receptors / Q000378:metabolism
chemical_list: C508587:IL37 protein, human; D007375:Interleukin-1; D008024:Ligands; D008070:Lipopolysaccharides; D051193:Toll-Like Receptors
keywords: alarmin; cytokine secretion; isoform; peripheral blood mononuclear cells