IL‐18 stimulates IL‐13‐mediated IFN‐γ‐sensitive host resistance in vivo

Abstract

IL-4 and IL-13 are up-regulated during in vivo responses to many nematode parasites, but increasing evidence suggests that increases in IL-13 can also occur independently of the IL-4-dominant Th2 response. Blocking B7 after Trichuris muris inoculation inhibits resistance and IL-4 elevations, instead resulting in an IFN-c-dominant response associated with susceptibility. However, blocking IFN-c under these conditions restores IL-13-dependent resistance. In this study, we examined the mechanism of IL-13 upregulation and associated protection during this in vivo immune response. CD4 + T cells and DX5 + TCR -cells were identified as the major producers of IL-13, and the DX5 + TCRcells were phenotyped as NK cells, since they expressed CD11b, IL-2Rb and Ly49C but not c-kit or FceRI. NK cell-derived IL-13 elevations were T cell-dependent, as CD4 + T cell depletion blocked IL-13 production by mesenteric lymph node cells and induced susceptibility. IL-13 expression was increased independently of IL-12; however, blocking IL-18 function inhibited IL-13 production and increased susceptibility. These results indicate that CD4 + T cells and NK cells are the major sources of IL-13 during the in vivo Th1 response induced by B7 blockade and that under these conditions, IL-18 is specifically required for the in vivo up-regulation of IL-13 production and associated host protection. IntroductionThe host protective response that develops following infection varies greatly with the particular pathogen. The type 2 immune response, associated with high levels of IL-4, IL-13 and other Th2 cytokines, provides protection against intestinal nematode parasites [1-3], while type 1 immunity, associated with an IFNc-dominant response, mediates resistance against many viruses and bacteria [4,5]. The events that lead to the development of type 1 and type 2 immunity are generally thought to be distinct, and as each response matures, production of characteristic cytokines can down-regulate the reciprocal response, resulting in further polarization.Typically, type 2 responses leading to resistance require the development of IL-4-producing effector CD4 + T cells, which then utilize autocrine IL-4 for their rapid expansion [3]. These Th2 cells mediate worm expulsion through their production of Th2 cytokines, with IL-4 and IL-13 being particularly important for the expulsion of gastrointestinal nematode parasites [1,2]. The development and expansion of IL-4-producing T cells is preferentially dependent on B7 costimulatory molecules [6,7], and in a number of infectious diseases, B7 blockade can actually deviate a Th2 response to an IFN-c-dominant Th1 response [8,9]. In the Th2 cell differentiation model just described, blockade of IL-4 production with B7 antagonists would be expected to also inhibit IL-13 production. However, other studies suggest that under certain circumstances IL-4 and IL-13 are regulated independently, and certain signaling pathways involving c-maf [10] and can differentially regulate these two cytokines. Consistent with these fin...

Homeostatic control of conjunctival mucosal goblet cells by NKT-derived IL-13

“…20, 21, and 25), the NK cell population was considered a good candidate to contain the IL-13-producing cells. NK cells can be identified by several markers, including NK1.1 and DX5 antibodies.…”

“…The NK1.1 antibody identifies NK cells in selected mouse strains, such as C57BL, FVB/N, and NZB. 20,21 The DX5 antibody targets the CD49b protein, 26 an α-integrin subunit that makes up half of the α2β1 integrin duplex. The CD49b protein is found in both NK and NKT cells of all mouse strains, including the NK1.1-negative strains (129A, AKR, BALB/c, C3H/He, C57BR, C58, CBA, DBA/1, DBA/2, MRL/lpr, and SJL).…”

Dynamics of gut mucosal and systemic Th1/Th2 cytokine responses in interferon-gamma and interleukin-12p40 knock out mice during primary and challenge Cryptosporidium parvum infection

“…This regulatory role of IL-18 seems to be restricted to IL-4 and IL-13 since there was no dysregulation of other Th2 cytokines studied (data not shown). During intestinal nematode infection IL-18 was demonstrated to work as a direct regulator of Th2 cytokines but not as an IFN-g-inducing cytokine (Helmby et al, 2001;Liu et al, 2006).…”

Immunoenhancing therapy with interleukin-18 against bacterial infection in immunocompromised hosts after severe surgical stress

“…Trichuris muris is also expelled by mucosal mast cells that are activated by the Th2 response. It has been reported that the beneficial effects of IL-18 on this infection are achieved by up-regulating IL-13 [48], although there are some conflicting reports showing deleterious effects of IL-18 on T. muris infection as a result of suppression of IL-4 and IL-13 (most likely, IFN-␥-inducing effects of IL-18) [49]. Nippostrongylus brasiliensis is expelled primarily by mucus derived from IL-13-activated goblet cells [50].…”