IL-33 is a crucial amplifier of innate rather than acquired immunity

Abstract

IL-33, a member of the IL-1-related cytokines, is considered to be a proallergic cytokine that is especially involved in Th2-type immune responses. Moreover, like IL-1α, IL-33 has been suggested to act as an "alarmin" that amplifies immune responses during tissue injury. In contrast to IL-1, however, the precise roles of IL-33 in those settings are poorly understood. Using IL-1- and IL-33-deficient mice, we found that IL-1, but not IL-33, played a substantial role in induction of T cell-mediated type IV hypersensitivity such as contact and delayed-type hypersensitivity and autoimmune diseases such as experimental autoimmune encephalomyelitis. Most notably, however, IL-33 was important for innate-type mucosal immunity in the lungs and gut. That is, IL-33 was essential for manifestation of T cell-independent protease allergen-induced airway inflammation as well as OVA-induced allergic topical airway inflammation, without affecting acquisition of antigen-specific memory T cells. IL-33 was significantly involved in the development of dextran-induced colitis accompanied by T cell-independent epithelial cell damage, but not in streptozocin-induced diabetes or Con A-induced hepatitis characterized by T cell-mediated apoptotic tissue destruction. In addition, IL-33-deficient mice showed a substantially diminished LPS-induced systemic inflammatory response. These observations indicate that IL-33 is a crucial amplifier of mucosal and systemic innate, rather than acquired, immune responses.

Fig. 1.

IL-33 is required for development of an IgE/mast cell-independent OVA-induced allergic airway hypersensitivity response. Mice were sensitized twice with OVA emulsified in alum on days 0 and 14. The mice were challenged intranasally with OVA or saline alone on days 28, 29, and 30. The number of cells in BAL fluids (A), airway hypersensitivity to methacholine (Mch) (B), and lung sections stained with hematoxylin-eosin (C) (100×; representative data from three to five mice are shown) at 24 h after the last OVA or PBS inhalation. Data show the mean ± SE: *P < 0.05 vs. corresponding values for saline-treated mice; ^†P < 0.05 vs. OVA-treated IL-33^−/− mice.

Fig. 2.

IL-33 is essential for the development of innate-type airway inflammation. The number of cells in BAL fluids during airway inflammation induced by HDM in IL-33^+/+ and IL-33^−/− mice (A) and induced by papain in C57BL/6-wild-type and Rag-2^−/− mice (B), IL-33^+/+ and IL-33^−/− mice (C, Left), and BALB/c-wild-type and IL-4^−/−IL-13^−/− mice (C, Right) at 24 h after the last OVA, HDM, papain, heat-inactivated papain, or saline inhalation. Data show the mean ± SE: *P < 0.05 vs. corresponding values for saline- or heat-inactivated papain-treated mice; ^†P < 0.05 vs. HDM- or papain-treated gene-deficient mice.

Fig. 3.

IL-33 is crucial for T/NKT cell-independent DSS-induced colitis. Mice were provided sterile water containing 3.5% or 3.0% DSS ad libitum for 7 d, followed by 14–15 d of regular drinking water. The change in body weight and survival during 3.5% or 3.0% DSS-induced colitis are compared. Data show the mean ± SE: * and ^†P < 0.05 vs. corresponding values for IL-33^+/+ mice.

Fig. 4.

IL-33 is involved in the induction of inflammation during DSS-induced colitis. Colon sections (A) (hematoxylin-eosin, 100×. Representative data from three to five mice are shown), score of the severity of colitis (B) (only inflamed sites were evaluated on day 15), and the levels of MPO activity (C) in colon homogenates from IL-33^+/+ and IL-33^−/− mice on day 8 or 15 during 3.0% DSS-induced colitis or in naïve mice. Data show the mean + SE: *P < 0.05 vs. corresponding values for naive mice; ^†P < 0.05 vs. corresponding values for IL-33^+/+ mice.

Fig. 5.

IL-33 is important for LPS-induced endotoxin shock. (A) Mice were injected intraperitoneally with LPS (5–20 mg/kg; n = 10–13), and survival was monitored. (B) Thioglycolate-induced peritoneal macrophages were stimulated with LPS for 9 or 48 h. IL-1α, IL-1β, IL-6, and TNF levels in the culture supernatants were determined by ELISA. Data show the mean ± SE: *, ^†P < 0.05 vs. corresponding values for IL-33^+/+ mice.