IL-33 amplifies both Th1- and Th2-type responses through its activity on human basophils, allergen-reactive Th2 cells, iNKT and NK cells.
IL-33 is an IL-1 family member recently identified as the ligand for T1/ST2 (ST2), a member of the IL-1 receptor family. ST2 is stably expressed on mast cells and T(h)2 effector T cells and its function has been studied in the context of T(h)2-associated inflammation. Indeed, IL-33 induces T(h)2 cytokines from mast cells and polarized mouse T cells and leads to pulmonary and mucosal T(h)2 inflammation when administered in vivo. To better understand how this pathway modulates inflammatory responses, we examined the activity of IL-33 on a variety of human immune cells. Human blood-derived basophils expressed high levels of ST2 receptor and responded to IL-33 by producing several pro-inflammatory cytokines including IL-1 beta, IL-4, IL-5, IL-6, IL-8, IL-13 and granulocyte macrophage colony-stimulating factor. Next, utilizing a human T(h)2-polarized T cell culture system derived from allergic donor blood cells, we found that IL-33 was able to enhance antigen-dependent and -independent T cell responses, including IL-5, IL-13 and IFN-gamma production. IL-33 activity was also tested on V alpha 24-positive human invariant NKT (iNKT) cells. In the presence of alpha-galactosylceramide antigen presentation, IL-33 dose dependently enhanced iNKT production of several cytokines, including both IL-4 and IFN-gamma. IL-33 also directly induced IFN-gamma production from both iNKT and human NK cells via cooperation with IL-12. Taken together, these results indicate that in addition to its activity on human mast cells, IL-33 is capable of activating human basophils, polarized T cells, iNKT and NK cells. Moreover, the nature of the responses elicited by IL-33 suggests that this axis may amplify both T(h)1- and T(h)2-oriented immune responses.
Department of Inflammation Research, Amgen Inc., 1201 Amgen Court West, Seattle, WA, USA.
Molly D
MD
Smithgall
Michael R
MR
Comeau
Bo-Rin Park
BR
Yoon
Dawn
D
Kaufman
Richard
R
Armitage
Dirk E
DE
Smith
D039741:Antigens, Dermatophagoides; D001249:Asthma / Q000209:etiology / Q000276:immunology; D001491:Basophils / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D018929:Cell Culture Techniques; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D004926:Escherichia coli; D005434:Flow Cytometry; D005699:Galactosylceramides / Q000494:pharmacology; D006801:Humans; D007249:Inflammation; D000072179:Interleukin-1 Receptor-Like 1 Protein; D000067596:Interleukin-33; D007378:Interleukins / Q000276:immunology* / Q000378:metabolism / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D011956:Receptors, Cell Surface / Q000276:immunology / Q000378:metabolism; D011994:Recombinant Proteins / Q000276:immunology* / Q000378:metabolism / Q000494:pharmacology; D018418:Th2 Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism
D039741:Antigens, Dermatophagoides; D016207:Cytokines; D005699:Galactosylceramides; C079241:IL1RL1 protein, human; C506536:IL33 protein, human; D000072179:Interleukin-1 Receptor-Like 1 Protein; D000067596:Interleukin-33; D007378:Interleukins; D011956:Receptors, Cell Surface; D011994:Recombinant Proteins; C493154:alpha-galactosylceramide