IL-33 released by alum is responsible for early cytokine production and has adjuvant properties.
Human vaccines have used aluminium-based adjuvants (alum) for >80 years despite incomplete understanding of how alum enhances the immune response. Alum can induce the release of endogenous danger signals via cellular necrosis which elicits inflammation-associated cytokines resulting in humoral immunity. IL-33 is proposed to be one such danger signal that is released from necrotic cells. Therefore, we investigated whether there is a role for IL-33 in the adjuvant activity of alum. We show that alum-induced cellular necrosis results in elevated levels of IL-33 following injection in vivo. Alum and IL-33 induce similar increases in IL-5, KC, MCP-1, MIP-1α and MIP-1β; many of which are dependent on IL-33 as shown in IL-33 knockout mice or by using an IL-33-neutralizing recombinant ST2 receptor. Furthermore, IL-33 itself functions as an adjuvant that, while only inducing a marginal primary response, facilitates a robust secondary response comparable to that observed with alum. However, IL-33 is not absolutely required for alum-induced antibody responses since alum mediates similar humoral responses in IL-33 knockout and wild-type mice. Our results provide novel insights into the mechanism of action behind alum-induced cytokine responses and show that IL-33 is sufficient to provide a robust secondary antibody response independently of alum.
Biotechnology Discovery Research, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, 46285.
William A
WA
Rose
Biotechnology Discovery Research, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, 46285.
Angela J
AJ
Okragly
Biotechnology Discovery Research, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, 46285.
Chetan N
CN
Patel
Biotechnology Discovery Research, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, 46285.
Robert J
RJ
Benschop
D000276:Adjuvants, Immunologic; D017607:Aluminum Compounds / Q000008:administration & dosage*; D000818:Animals; D001323:Autoantibodies / Q000276:immunology*; D016207:Cytokines / Q000276:immunology*; D004305:Dose-Response Relationship, Drug; D000067596:Interleukin-33 / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009336:Necrosis / Q000175:diagnosis / Q000276:immunology; D013154:Spleen / Q000187:drug effects / Q000276:immunology* / Q000473:pathology*
D000276:Adjuvants, Immunologic; D017607:Aluminum Compounds; D001323:Autoantibodies; D016207:Cytokines; C506535:Il33 protein, mouse; D000067596:Interleukin-33