Inhibition ofin vitroimmunoglobulin production by IL-12 in murine chronic graft-vs. -host disease: synergism with IL-18

212

144

We investigated the effects of IFN-γ-inducing factor (IL-18) in a ragweed (RW) mouse model of allergic asthma. Administration of IL-18 in conjunction with allergic sensitization and challenge in wild-type, but not IFN-γ −/− mice, inhibited the bronchoalveolar lavage (BAL) eosinophilia induced by RW challenge, and increased serum levels of RW-specific IgG2a and production of IFN-γ from splenocytes cultured with RW, indicating a critical role for IFN-γ in mediating these effects. Paradoxically, the same treatment schedule in WT mice increased serum levels of RW-specific IgE and IgG1, and production of IL-4 and IL-5 from splenocytes cultured with RW. When the effects of the same IL-18 treatment schedule were allowed to mature for 3 wk, the inhibition of lung eosinophil recruitment was replaced by augmentation of lung eosinophil recruitment. In another experiment, IL-18 administered only with allergic sensitization increased BAL eosinophilia and lung expression of IL-5 and IFN-γ, while IL-18 administered only with RW challenge decreased BAL eosinophilia and increased lung IFN-γ expression, while lung expression of IL-5 remained unchanged. IL-18 administered without RW or adjuvant to naive mice increased total serum IgE levels. Finally, intrapulmonary administrations of IL-18 plus RW in naive mice dramatically increased Th2 cytokine production, IgE levels, eosinophil recruitment, and airway mucus, demonstrating induction of allergic sensitization. This is the first report demonstrating that IL-18 promotes a Th2 phenotype in vivo, and potently induces allergic sensitization. These results suggest that IL-18 may contribute to the pathogenesis of allergic asthma.

Section: Discussionmentioning

confidence: 52%

IFN-γ-Inducing Factor (IL-18) Increases Allergic Sensitization, Serum IgE, Th2 Cytokines, and Airway Eosinophilia in a Mouse Model of Allergic Asthma

Wild

Sigounas

Sur

et al. 2000

212

144

“…In vitro studies have demonstrated that the combination of IL-12 and IL-18 suppress IgG1 and enhance IgG2a levels (38). However, studies of murine graft-vs-host disease suggest that IL-18 lacks this discriminatory effect and, in fact, suppresses total Ig, IgG1, and IgG2a levels in vitro (39). While IL-18 would be expected to induce IgG2a production in vivo (given its role in inducing IFN-␥), there were no significant changes in Ag-specific total Ig, IgG1, or IgG2a titers when IL-18 was administered to IL-12 ϩ/ϩ mice.…”

Section: Discussionmentioning

confidence: 99%

IL-18 Has IL-12-Independent Effects in Delayed-Type Hypersensitivity: Studies in Cell-Mediated Crescentic Glomerulonephritis

Kitching

Tipping

Kurimoto

et al. 2000

IL-18 (formerly known as IFN-γ-inducing factor) enhances Th1 responses via effects that are thought to be dependent on and synergistic with IL-12. The potential for IL-18 to exert IL-12-independent effects in delayed-type hypersensitivity (DTH) responses was studied in a model of Th1-directed, DTH-mediated crescentic glomerulonephritis induced by planting an Ag in glomeruli of sensitized mice as well as in cutaneous DTH. Sensitized genetically normal (IL-12+/+) mice developed proteinuria and crescentic glomerulonephritis with a glomerular influx of DTH effectors (CD4+ T cells, macrophages, and fibrin deposition) in response to the planted glomerular Ag. IL-12p40-deficient (IL-12−/−) mice showed significant reductions in crescent formation, proteinuria, and glomerular DTH effectors. Administration of IL-18 to IL-12−/− mice restored the development of histological (including effectors of DTH) and functional glomerular injury in IL-12−/− mice to levels equivalent to those in IL-12+/+ mice. IL-18 administration to IL-12−/− mice increased glomerular ICAM-1 protein expression, but did not restore Ag-stimulated splenocyte IFN-γ, GM-CSF, IL-2, or TNF-α production. Sensitized IL-12+/+ mice also developed cutaneous DTH following intradermal challenge with the nephritogenic Ag. Cutaneous DTH was inhibited in IL-12−/− mice, but was restored by administration of IL-18. IL-12+/+ mice given IL-18 developed augmented injury, with enhanced glomerular and cutaneous DTH, demonstrating the synergistic effects of IL-18 and IL-12 in DTH responses. These studies demonstrate that even in the absence of IL-12, IL-18 can induce in vivo DTH responses and up-regulate ICAM-1 without inducing IFN-γ, GM-CSF, or TNF-α production.

“…Given the striking synergy between IL-12 and IL-18 for IFN-␥ induction (23) and given the inhibitory effects of IFN-␥ on Ig production in certain experimental systems (24,25), we evaluated whether the inhibitory effects exerted by IL-12/IL-18-derived NK cells on Ig production and cell survival were mediated by IFN-␥. As indicated in Fig.…”

Section: Distinct Effects Of Nk/t-nk Cells On Ig Production By Syngenmentioning

confidence: 99%

Cytokine Production and Killer Activity of NK/T-NK Cells Derived with IL-2, IL-15, or the Combination of IL-12 and IL-18

Lauwerys

Garot

Renauld

et al. 2000

Self Cite

186

115

NK cell populations were derived from murine splenocytes stimulated by IL-2, IL-15, or the combination of IL-12 and IL-18. Whereas NK cells derived with the latter cytokines consisted of an homogeneous population of NK cells (DX5+CD3−), those derived with IL-2 or IL-15 belonged to two different populations, namely NK cells (DX5+CD3−) and T-NK cells (DX5+CD3+). Among NK cells, only those derived with IL-12/IL-18 produced detectable levels of cytokines, namely IFN-γ, IL-10, and IL-13 (with the exception of IL-13 production by NK cells derived with IL-2). As for T-NK cells, IL-2-stimulated cells produced a wide range of cytokines, including IL-4, IL-5, IL-9, IL-10, and IL-13, but no IFN-γ, whereas IL-15-derived T-NK cells failed to produce any cytokine. Switch-culture experiments indicated that T-NK cells derived in IL-2 and further stimulated with IL-12/IL-18 produced IFN-γ and higher IL-13 levels. Next, we observed that NK/T-NK cell populations exerted distinct effects on Ig production by autologous splenocytes according to the cytokines with which they were derived. Thus, addition of NK cells derived in IL-12/IL-18 inhibited Ig production and induced strong cytotoxicity against splenocytes, whereas addition of NK or T-NK cells grown in IL-2 or IL-15 did not. Experiments performed in IFN-γR knockout mice demonstrated that IFN-γ was not involved in the killer activity of IL-12/IL-18-derived NK cells. The hypothesis that their cytotoxic activity was related to the induction of target apoptosis was confirmed on murine A20 lymphoma cells. Experiments performed in MRL/lpr mice indicated that IL-12/IL-18-derived NK cells displayed their distinct killer activity through a Fas-independent pathway. Finally, perforin was much more expressed in IL-12/IL-18-derived NK cells as compared with IL-2- or IL-15-derived NK cells, an observation that might explain their unique cytotoxicity.