Biomedical subjects

Frank Brombacher

Publications and source records attributed to Frank Brombacher.

At least 19 recordsLinked to original sources

PubMed2007

IL-25 regulates Th17 function in autoimmune inflammation.

Interleukin (IL)-25 is a member of the IL-17 family of cytokines. However, unlike the other members of this family, IL-25 promotes T helper (Th) 2 responses. We now show that IL-25 also regulates the development of autoimmune inflammation mediated by IL-17-producing T cells. We have generated IL-25-deficient (il25-/-) mice and found that they are highly susceptible to experimental autoimmune encephalomyelitis (EAE). The accelerated disease in the il25-/- mice is associated with an increase of IL-23 in the periphery and a subsequent increase in the number of inflammatory IL-17-, IFNgamma-, and TNF-producing T cells that invade the central nervous system. Neutralization of IL-17 but not IFNgamma in il25-/- mice prevented EAE, suggesting that IL-17 is a major disease-promoting factor. IL-25 treatment at several time points during a relapse-remitting model or chronic model of EAE completely suppressed disease. IL-25 treatment induced elevated production of IL-13, which is required for suppression of Th17 responses by direct inhibition of IL-23, IL-1beta, and IL-6 expression in activated dendritic cells. Thus, IL-25 and IL-17, being members of the same cytokine family, play opposing roles in the pathogenesis of organ-specific autoimmunity.

Animals↗

PubMed2007

Delayed goblet cell hyperplasia, acetylcholine receptor expression, and worm expulsion in SMC-specific IL-4Ralpha-deficient mice.

Interleukin 4 receptor alpha (IL-4Ralpha) is essential for effective clearance of gastrointestinal nematode infections. Smooth muscle cells are considered to play a role in the type 2 immune response-driven expulsion of gastrointestinal nematodes. Previous studies have shown in vitro that signal transducer and activator of transcription 6 signaling in response to parasitic nematode infection significantly increases smooth muscle cell contractility. Inhibition of the IL-4Ralpha pathway inhibits this response. How this response manifests itself in vivo is unknown. In this study, smooth muscle cell IL-4Ralpha-deficient mice (SM-MHC(Cre)IL-4Ralpha(-/lox)) were generated and characterized to uncover any role for IL-4/IL-13 in this non-immune cell type in response to Nippostrongylus brasiliensis infection. IL-4Ralpha was absent from alpha-actin-positive smooth muscle cells, while other cell types showed normal IL-4Ralpha expression, thus demonstrating efficient cell-type-specific deletion of the IL-4Ralpha gene. N. brasiliensis-infected SM-MHC(Cre)IL-4Ralpha(-/lox) mice showed delayed ability to resolve infection with significantly prolonged fecal egg recovery and delayed worm expulsion. The delayed expulsion was related to a delayed intestinal goblet cell hyperplasia, reduced T helper 2 cytokine production in the mesenteric lymph node, and reduced M3 muscarinic receptor expression during infection. Together, these results demonstrate that in vivo IL-4Ralpha-responsive smooth muscle cells are beneficial for N. brasiliensis expulsion by coordinating T helper 2 cytokine responses, goblet hyperplasia, and acetylcholine responsiveness, which drive smooth muscle cell contractions.

Animals↗

PubMed2006

Interleukin-17 is a negative regulator of established allergic asthma.

T helper (Th)17 cells producing interleukin (IL)-17 play a role in autoimmune and allergic inflammation. Here, we show that IL-23 induces IL-17 in the lung and IL-17 is required during antigen sensitization to develop allergic asthma, as shown in IL-17R-deficient mice. Since IL-17 expression increased further upon antigen challenge, we addressed its function in the effector phase. Most strikingly, neutralization of IL-17 augmented the allergic response in sensitized mice. Conversely, exogenous IL-17 reduced pulmonary eosinophil recruitment and bronchial hyperreactivity, demonstrating a novel regulatory role of IL-17. Mechanistically, IL-17 down modulated eosinophil-chemokine eotaxin (CCL11) and thymus- and activation-regulated chemokine/CCL17 (TARC) in lungs in vivo and ex vivo upon antigen restimulation. In vitro, IL-17 reduced TARC production in dendritic cells (DCs)-the major source of TARC-and antigen uptake by DCs and IL-5 and IL-13 production in regional lymph nodes. Furthermore, IL-17 is regulated in an IL-4-dependent manner since mice deficient for IL-4Ralpha signaling showed a marked increase in IL-17 concentration with inhibited eosinophil recruitment. Therefore, endogenous IL-17 is controlled by IL-4 and has a dual role. Although it is essential during antigen sensitization to establish allergic asthma, in sensitized mice IL-17 attenuates the allergic response by inhibiting DCs and chemokine synthesis.

Allergens↗

PubMed2006

Type 2 immune response associated with silicosis is not instrumental in the development of the disease.

It has been proposed that the development of lung fibrosis is associated with a T helper type 2 response, mainly characterized by IL-4 and IL-13 production. We investigated the potential role of type 2 immune polarization in the silicotic process and examined the pulmonary response to silica particles in mice genetically deficient for IL-4. We found that IL-4(-/-) mice were not protected against the development of silicosis, suggesting that IL-4 is not essential for the development of this fibrotic disease. By evaluating the intensity of silica-induced lung fibrosis in mice deficient for IL-4 receptor alpha (IL-4Ralpha), we showed that the establishment of pulmonary fibrosis was independent of both IL-4 and IL-13. Strong impairment of the type 2 immune response (IgG(1)) in the lungs of IL-4(-/-) and IL-4Ralpha(-/-) mice did not affect the development of the disease. Measurement of IL-13alpha2 receptor expression and IgG(2a), IL-12p70, and IFN-gamma levels in silica-treated IL-4(-/-) and IL-4Ralpha(-/-) animals showed that the development of silicosis was not related to an IL-13 signaling pathway or a switch to a type 1 response in deficient animals. Our data clearly indicate that the type 2 immune response associated with silicosis in mice is not required for the development of this inflammatory and fibrotic disease.

Animals↗

PubMed2006

IL-4R signaling is required to induce IL-10 for the establishment of T(h)2 dominance.

The requirement for IL-4 to promote differentiation of naive CD4(+) T cells into T(h)2 effector cell populations was established by classical in vitro studies. More recent in vivo data, however, indicate that signaling through the IL-4R is not essential for acquisition of the T(h)2 phenotype. In order to reconcile these seemingly contradictory conclusions, we have taken advantage of the ability of the excretory/secretory antigens of the gastrointestinal nematode Nippostrongylus brasiliensis to down-regulate T(h)1 cell development and drive T(h)2 cell expansion. We show that the initial development of IL-4-producing T cells is independent of IL-4R signaling but that the subsequent expansion of IL-4-producing CD4(+) T cells in a competitive environment that also contains T(h)1 potential is positively influenced by IL-4R signaling. We find that the production of IL-10 is the key IL-4R-dependent factor required to maintain T(h)2 dominance and that in the absence of IL-4R signaling, T(h)2 expansion can only be achieved by neutralization of T(h)1 cytokines. Moreover, in the absence of IL-4R signaling, reduced IL-10 production is due to the lack in expansion of an IL-10(+) T(h)2 population, rather than a global defect in the production of IL-10 by CD4(+) T cells. Thus, the evolution of T(h)2 dominance is achieved at the expense of T(h)1 cell development, normally restrained by IL-10 in an IL-4R-dependent manner. We conclude that T(h)2 cell development in response to N. brasiliensis antigen requires both IL-4 and IL-10 to act in concert on incipient populations of both T(h)1 and T(h)2 types.

Animals↗

PubMed2006

Interferon-gamma and nitric oxide in combination with antibodies are key protective host immune factors during trypanosoma congolense Tc13 Infections.

The control of chronic Trypanosoma congolense trypanosomiasis was analyzed using several gene-deficient mouse strains. First, interferon (IFN)-gamma receptor (IFN-gamma-R)-deficient mice were used to show that IFN- gamma -mediated immune activation is crucial for parasitemia control. Second, infections in major histocompatibility complex (MHC) class II-deficient mice indicate that this molecule is needed for initiation of IFN- gamma and subsequent tumor necrosis factor (TNF) production. Downstream of IFN-gamma-R signaling, inducible NO synthase (iNOS)-dependent trypanosome killing occurs, as is shown by the hypersusceptible phenotype of iNOS-deficient mice. Besides proinflammatory responses, B cells and, more specifically, immunoglobulin (Ig) G antibodies are crucial for parasite killing. Hence, parasitemia control is abolished in B cell-deficient mice, whereas IgM-deficient mice control the infection as efficiently as do wild-type mice. In addition, splenectomized mice that have a normal IgM response but an impaired IgG2a/3 response fail to control T. congolense infection. Collectively, these results suggest that host protective immunity against T. congolense is critically dependent on the combined action of the proinflammatory mediators/effectors IFN- gamma , TNF, and NO and antiparasite IgGs.

Animals↗

PubMed2006

Cutting edge: IL-4-induced protection of CD4+CD25- Th cells from CD4+CD25+ regulatory T cell-mediated suppression.

CD4(+)CD25(+) T regulatory (Treg) cells are a CD4(+) T cell subset involved in the control of the immune response. In vitro, murine CD4(+)CD25(+) Treg cells inhibit CD4(+)CD25(-) Th cell proliferation induced by anti-CD3 mAb in the presence of APCs. The addition of IL-4 to cocultured cells inhibits CD4(+)CD25(+) Treg cell-mediated suppression. Since all cell types used in the coculture express the IL-4Ralpha chain, we used different combinations of CD4(+)CD25(-) Th cells, CD4(+)CD25(+) Treg cells, and APCs from wild-type IL-4Ralpha(+/+) or knockout IL-4Ralpha(-/-) mice. Results show that the engagement of the IL-4Ralpha chain on CD4(+)CD25(-) Th cells renders these cells resistant to suppression. Moreover, the addition of IL-4 promotes proliferation of IL-4Ralpha(+/+)CD4(+)CD25(+) Treg cells, which preserve full suppressive competence. These findings support an essential role of IL-4 signaling for CD4(+)CD25(-) Th cell activation and indicate that IL-4-induced proliferation of CD4(+)CD25(+) Treg cells is compatible with their suppressive activity.

Animals↗

PubMed2006

Identification of a common gene signature for type II cytokine-associated myeloid cells elicited in vivo in different pathologic conditions.

Compared with type I cytokine-associated myeloid (M1) cells, the molecular repertoire and mechanisms underlying functional properties of type II cytokine-associated myeloid (M2) cells are poorly characterized. Moreover, most studies have been limited to in vitro-elicited M2 cells. Here, comparative gene expression profiling of M1 and M2 cells, elicited in murine models of parasitic infections and cancer, yielded a common signature for in vivo-induced M2 populations independent of disease model, mouse strain, and organ source of cells. Some of these genes, such as cadherin-1, selenoprotein P, platelet-activating factor acetylhydrolase, and prosaposin, had not been documented as associated with M2. Overall, the common signature genes provide a molecular basis for a number of documented or suggested properties of M2, including immunomodulation, down-regulation of inflammation, protection against oxidative damage, high capacity for phagocytosis, and tissue repair. Interestingly, several common M2 signature genes encode membrane-associated markers that could be useful for the identification and isolation of M2. Some of these genes were not induced by IL-4/IL-13 or IL-10 under various in vitro settings and thus were missed in approaches based on in vitro-activated cells, validating our choice of in vivo models for expression profiling of myeloid cells.

Animals↗

PubMed2006

Impairment of alternative macrophage activation delays cutaneous leishmaniasis in nonhealing BALB/c mice.

Expressed on various cell types, the IL-4Ralpha is a component of both receptors for IL-4 and IL-13. Susceptibility of BALB/c mice to Leishmania major is believed to be dependent on the development of IL-4- and IL-13-producing Th2 cells, while IFN-gamma secretion by Th1 cells is related to resistance. Despite a sustained development of Th2 cells, IL-4Ralpha-deficient BALB/c mice are able to control acute cutaneous leishmaniasis, suggesting that IL-4Ralpha-bearing cells other than Th2 cells contribute to susceptibility. To analyze the contribution of the IL-4Ralpha on macrophages, recently generated macrophage/neutrophil-specific IL-4Ralpha-deficient mice on a susceptible BALB/c genetic background were infected with L. major. Strikingly, macrophage/neutrophil-specific IL-4Ralpha-deficient mice showed a significantly delayed disease progression with normal Th2 and type 2 Ab responses but improved macrophage leishmanicidal effector functions and reduced arginase activity. Together, these results suggest that alternative macrophage activation contributes to susceptibility in cutaneous leishmaniasis.

Animals↗

PubMed2006

Exposure to the fish parasite Anisakis causes allergic airway hyperreactivity and dermatitis.

BACKGROUND: Several case reports show allergy and anaphylactic reactions to the fish parasite Anisakis in the domestic and occupational setting. Further research is needed on the prevalence and mechanisms of disease. OBJECTIVE: To determine the prevalence of Anisakis sensitization and related symptoms among workers in 2 fish-processing factories, and to use gene-deficient mice to determine the working mechanisms of Anisakis allergy. METHODS: A modified version of the European Community Respiratory Health Survey was used to interview 578 South African fish-processing workers. Sensitization to Anisakis, seafood, and common aeroallergens was determined by skin prick test. Lung function was measured by spirometry and methacholine challenge. Serum eicosapentaenoic acid levels were used as an index of seafood consumption. Sensitized wild-type, IL-4, or IL-4 receptor alpha-deficient mice were challenged orally with Anisakis extract. Allergic reactions, lung pathology, antibodies, cytokines, mast cell proteases, and histamine were evaluated. RESULTS: The prevalence of sensitization to Anisakis was higher than the prevalence of sensitization to fish (8% vs 6%). Anisakis-specific IgE reactivity was associated with bronchial hyperreactivity and dermatitis, and significantly increased with fish consumption. In mice, Anisakis infective larvae (L3) induced a striking T(H)2/type 2 response. Food-allergic-type reactions induced by oral challenge with Anisakis extract were absent in IL-4 receptor alpha knockout mice. CONCLUSION: Anisakis sensitization in fish-processing workers is associated with allergic symptoms and correlates with high levels of fish consumption. Anisakis proteins induce allergic reactions in sensitized mice by IL-4/IL-13-mediated mechanisms. CLINICAL IMPLICATIONS: Anisakis allergy should be considered in fish-processing workers with allergic symptoms.

Administration, Oral↗

PubMed2006

Infection with Syphacia obvelata (pinworm) induces protective Th2 immune responses and influences ovalbumin-induced allergic reactions.

Infections with pinworms are common in rodent animal facilities. In this study, we show the consequence of an outbreak in a transgenic barrier facility of infection by Syphacia obvelata, a murine pinworm gastrointestinal nematode. Immune responses were defined in experimental infection studies with BALB/c mice. Infection with S. obvelata induced a transient Th2-type immune response with elevated interleukin 4 (IL-4), IL-5, and IL-13 cytokine production and parasite-specific immunoglobulin G1 (IgG1). In contrast, BALB/c mice deficient in IL-13, IL-4/13, or the IL-4 receptor alpha chain showed chronic disease, with a >100-fold higher parasite burden, increased gamma interferon production, parasite-specific IgG2b, and a default Th2 response. Interestingly, infected IL-4-/- BALB/c mice showed only slightly elevated parasite burdens compared to the control mice, suggesting that IL-13 plays the dominant role in the control of S. obvelata. The influence that pinworm infection has on the allergic response to a dietary antigen was found to be important. Helminth-infected mice immunized against ovalbumin (Ova) elicited more severe anaphylactic shock with reduced Ova-specific IL-4 and IL-5 than did noninfected controls, demonstrating that S. obvelata infection is able to influence nonrelated laboratory experiments. The latter outcome highlights the importance of maintaining mice for use as experimental models under pinworm-free conditions.

Animals↗

PubMed2006

Tumors induce a subset of inflammatory monocytes with immunosuppressive activity on CD8+ T cells.

Active suppression of tumor-specific T lymphocytes can limit the efficacy of immune surveillance and immunotherapy. While tumor-recruited CD11b+ myeloid cells are known mediators of tumor-associated immune dysfunction, the true nature of these suppressive cells and the fine biochemical pathways governing their immunosuppressive activity remain elusive. Here we describe a population of circulating CD11b+IL-4 receptor alpha+ (CD11b+IL-4Ralpha+), inflammatory-type monocytes that is elicited by growing tumors and activated by IFN-gamma released from T lymphocytes. CD11b+IL-4Ralpha+ cells produced IL-13 and IFN-gamma and integrated the downstream signals of these cytokines to trigger the molecular pathways suppressing antigen-activated CD8+ T lymphocytes. Analogous immunosuppressive circuits were active in CD11b+ cells present within the tumor microenvironment. These suppressor cells challenge the current idea that tumor-conditioned immunosuppressive monocytes/macrophages are alternatively activated. Moreover, our data show how the inflammatory response elicited by tumors had detrimental effects on the adaptive immune system and suggest novel approaches for the treatment of tumor-induced immune dysfunctions.

Animals↗

PubMed2006

TH1-dominant granulomatous pathology does not inhibit fibrosis or cause lethality during murine schistosomiasis.

Schistosoma mansoni egg-induced inflammation is accompanied by TH2 cell polarization and development of fibrotic granulomas in host tissue. The interleukin (IL)-4 receptor alpha (IL-4Ralpha), which mediates IL-4 and IL-13 signaling, is essential for granulomatous pathology through a putative CD4+ T-cell-dependent mechanism. In this study, we asked whether CD4+ T-cell-specific IL-4Ralpha-deficient mice (Lck(Cre)IL-4Ralpha(-/lox)) developed granulomas and egg-driven collagen production. Although eosinophilia and goblet cell hyperplasia were impaired in Lck(Cre)IL-4Ralpha(-/lox) mice, there was no reduction in size or collagen content of lung and liver granulomas. The lack of CD4+ T-cell IL-4Ralpha expression caused significant increases in interferon-gamma-producing cells, inducible nitric-oxide synthetase production, and hepatic damage, compared with similarly infected wild-type mice. Interestingly, this TH1-associated liver injury did not lead to premature mortality in this strain. Instead, lower levels of serum endotoxin in Lck(Cre)IL-4Ralpha(-/lox) mice suggest that intestinal barrier function may be the dominant factor for survival during natural infection.

Animals↗

PubMed2005

IL-4 receptor signaling in Clara cells is required for allergen-induced mucus production.

Excessive mucus production is an important pathological feature of asthma. The Th2 cytokines IL-4 and IL-13 have both been implicated in allergen-induced mucus production, inflammation, and airway hyperreactivity. Both of these cytokines use receptors that contain the IL-4Ralpha subunit, and these receptors are expressed on many cell types in the lung. It has been difficult to determine whether allergen-induced mucus production is strictly dependent on direct effects of IL-4 and IL-13 on epithelial cells or whether other independent mechanisms exist. To address this question, we used a cell type-specific inducible gene-targeting strategy to selectively disrupt the IL-4Ralpha gene in Clara cells, an airway epithelial cell population that gives rise to mucus-producing goblet cells. Clara cell-specific IL-4Ralpha-deficient mice and control mice developed similar elevations in serum IgE levels, airway inflammatory cell numbers, Th2 cytokine production, and airway reactivity following OVA sensitization and challenge. However, compared with control mice, Clara cell-specific IL-4Ralpha-deficient mice were nearly completely protected from allergen-induced mucus production. Because only IL-13 and IL-4 are thought to signal via IL-4Ralpha, we conclude that direct effects of IL-4 and/or IL-13 on Clara cells are required for allergen-induced mucus production in the airway epithelium.

Allergens↗

PubMed2005

The induction of a type 1 immune response following a Trypanosoma brucei infection is MyD88 dependent.

The initial host response toward the extracellular parasite Trypanosoma brucei is characterized by the early release of inflammatory mediators associated with a type 1 immune response. In this study, we show that this inflammatory response is dependent on activation of the innate immune system mediated by the adaptor molecule MyD88. In the present study, MyD88-deficient macrophages are nonresponsive toward both soluble variant-specific surface glycoprotein (VSG), as well as membrane-bound VSG purified from T. brucei. Infection of MyD88-deficient mice with either clonal or nonclonal stocks of T. brucei resulted in elevated levels of parasitemia. This was accompanied by reduced plasma IFN-gamma and TNF levels during the initial stage of infection, followed by moderately lower VSG-specific IgG2a Ab titers during the chronic stages of infection. Analysis of several TLR-deficient mice revealed a partial requirement for TLR9 in the production of IFN-gamma and VSG-specific IgG2a Ab levels during T. brucei infections. These results implicate the mammalian TLR family and MyD88 signaling in the innate immune recognition of T. brucei.

Adaptor Proteins, Signal Transducing↗

PubMed2005

Reactive oxygen species and 12/15-lipoxygenase contribute to the antiproliferative capacity of alternatively activated myeloid cells elicited during helminth infection.

Understanding the role of CD11b(+)GR-1(+) myeloid suppressor cells in the immune suppression and immunoregulation associated with a variety of diseases may provide therapeutic opportunities. In this article, we show, in a model of helminth infection, that CD11b(+)GR-1(+) myeloid suppressor cells but not CD11b(+)F4/80(high) mature macrophages expanded in the peritoneal cavity of BALB/c mice implanted with Taenia crassiceps. Peritoneal cell populations from early stage-infected animals impaired T cell proliferation by secreting NO. Yet, they lost their ability to secrete NO in the late stage of infection. Concomitantly, their capacity to exert arginase activity and to express mRNAs coding for FIZZ1 (found in inflammatory zone 1), Ym, and macrophage galactose-type C-type lectin increased. Furthermore, cells from early stage-infected mice triggered T cells to secrete IFN-gamma and IL-4, whereas in the late stage of infection, they only induced IL-4 production. These data suggest that CD11b(+)GR-1(+) myeloid suppressor cells displaying an alternative activation phenotype emerged gradually as T. crassiceps infection progressed. Corroborating the alternative activation status in the late stage of infection, the suppressive activity relied on arginase activity, which facilitated the production of reactive oxygen species including H(2)O(2) and superoxide. We also document that the suppressive activity of alternative myeloid suppressor cells depended on 12/15-lipoxygenase activation generating lipid mediators, which triggered peroxisome proliferator-activated receptor-gamma. IL-4 and IL-13 signaling contributed to the expansion of myeloid suppressor cells in the peritoneal cavity of T. crassiceps-infected animals and to their antiproliferative activity by allowing arginase and 12/15-lipoxygenase gene expression.

Animals↗

PubMed2005

IL-9 is a susceptibility factor in Leishmania major infection by promoting detrimental Th2/type 2 responses.

IL-9 is a cytokine produced by Th2 cells, induced during Leishmania major infection. Because the role of IL-9 in leishmaniasis is currently unknown, IL-9-deficient mice were generated by immunization with mouse IL-9 coupled to OVA. This produced strong and long-lasting neutralizing anti-IL-9 Abs in vivo. Anti-IL-9 vaccination showed protective effects, because it enabled L. major-infected nonhealer BALB/c mice to better resist to leishmaniasis with doubling the time span until pathological disease progression occurred. Increased resistance was also demonstrated by moderate footpad swelling and histopathology due to reduced parasite burden compared with sham-immunized BALB/c mice. Mechanistically, IL-9 neutralization in BALB/c mice resulted in a reduction of detrimental Th2/type 2 responses with an observed shift toward protective Th1 immune responses. This led to an alteration from alternative to classical macrophage activation with subsequent enhanced killing effector functions, as demonstrated by increased NO production but reduced arginase 1-mediated macrophage responses. Conclusively, the data show that IL-9 is a susceptible factor in leishmaniasis. They further suggest that IL-9 is able to influence Th dichotomy in leishmaniasis by promoting detrimental Th2/type 2 responses in BALB/c mice. The results extend efforts made to generate autoantibodies capable of regulating biological processes, with IL-9 a potential drug target against leishmaniasis.

Animals↗

PubMed2005

IL-9 protects against bleomycin-induced lung injury: involvement of prostaglandins.

IL-9 is a Th2 cytokine that exerts pleiotropic activities, and might be involved in the regulation of lung inflammatory processes. To characterize the activity of IL-9 on lung injury, we compared the pulmonary responses to bleomycin (blm) in IL-9 transgenic (Tg5) and wild-type (FVB) mice. Following intratracheal instillation of lethal doses of blm, the mortality rate was markedly reduced in Tg5 mice compared to their wild-type counterparts (ie, 25% mortality for Tg5 versus 85% for FVB mice, 21 days after instillation of 0.05U blm/mouse). Histological and biochemical analyses showed that blm induced less lung injury and less epithelial damage in Tg5 as compared to FVB animals. This protection of Tg5 mice was accompanied by an expansion of eosinophils and B cells in the lungs. In addition, TGF-beta and prostaglandin-E2 (PGE2) levels in broncho-alveolar lavage fluid were also increased in transgenic mice. The contribution of B cells and eosinophils to the protective mechanism did not appear essential since eosinophil-deficient (IL-5 KO) and B-deficient (muMT) mice overexpressing IL-9 were also resistant to high doses of blm. We could rule out that TGF-beta was a key factor in the protective effect of IL-9 by blocking this mediator with neutralizing antibodies. Indomethacin treatment, which inhibited PGE2 production in both strains, suppressed the protection in Tg5 mice, supporting the idea that IL-9 controls blm-induced lung injury through a prostaglandin-dependent mechanism.

Animals↗