Interleukin‐4 and ‐10 exacerbate candidiasis in mice

Tonnetti, Laura; Spaccapelo, Roberta; Cenci, Elio; Mencacci, Antonella; Puccetti, Paolo; Coffman, Robert L.; Bistoni, Francesco; Romani, Luigina

doi:10.1002/eji.1830250614

Cited by 119 publications

(63 citation statements)

References 42 publications

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“…Increased IL-10 production, modulated through different TLRs and dectin-1, shifts the balance toward anti-inflammatory cytokine responses (52). On the other hand, the upregulation of IL-10 also exacerbates Candida infection in mice (53). IL-10-deficient mice are more resistant to Candida infection, due to an upregulated Th1 antifungal response (54).…”

Section: Discussionmentioning

confidence: 99%

Growth of Candida albicans Cells on the Physiologically Relevant Carbon Source Lactate Affects Their Recognition and Phagocytosis by Immune Cells

et al. 2013

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bCandida albicans is a normal resident of the human gastrointestinal and urogenital tracts and also a prevalent fungal pathogen. During both commensalism and infection, it must match the immunological defenses of its host while adapting to environmental cues and the local nutrient status. C. albicans regularly colonizes glucose-poor niches, thereby depending upon alternative carbon sources for growth. However, most studies of host immune responses to C. albicans have been performed on fungal cells grown on glucose, and the extent to which alternative physiologically relevant carbon sources impact innate immune responses has not been studied. The fungal cell wall is decorated with multifarious pathogen-associated molecular patterns and is the main target for recognition by host innate immune cells. Cell wall architecture is both robust and dynamic, and it is dramatically influenced by growth conditions. We found that growth of C. albicans cells on lactate, a nonfermentative carbon source available in numerous anatomical niches, modulates their interactions with immune cells and the resultant cytokine profile. Notably, lactate-grown C. albicans stimulated interleukin-10 (IL-10) production while decreasing IL-17 levels, rendering these cells less visible to the immune system than were glucose-grown cells. This trend was observed in clinical C. albicans isolates from different host niches and from different epidemiological clades. In addition, lactate-grown C. albicans cells were taken up by macrophages less efficiently, but they were more efficient at killing and escaping these phagocytic cells. Our data indicate that carbon source has a major impact upon the C. albicans interaction with the innate immune system.

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Section: Discussionmentioning

confidence: 99%

Growth of Candida albicans Cells on the Physiologically Relevant Carbon Source Lactate Affects Their Recognition and Phagocytosis by Immune Cells

et al. 2013

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“…Skewing an established immune response might be more difficult than inducing a polarized response in naive mice. Indeed, it is reported that IL-4 fails to convert an already established Th1 response into a Th2 response (36). Nevertheless, the pathogenic potential of the Th1-type immune response in Graves' hyperthyroidism suggests the need for caution in developing therapeutic strategies aimed at deviating a presumed Th2-mediated autoimmune response to Th1-dominant immunity.…”

Section: Discussionmentioning

confidence: 99%

Prevention of Autoantibody-Mediated Graves’-Like Hyperthyroidism in Mice with IL-4, a Th2 Cytokine

Nagayama

Mizuguchi

Hayakawa

et al. 2003

The Journal of Immunology

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Graves’ hyperthyroidism has long been considered to be a Th2-type autoimmune disease because it is directly mediated by autoantibodies against the thyrotropin receptor (TSHR). However, several lines of evidence have recently challenged this concept. The present study evaluated the Th1/Th2 paradigm in Graves’ disease using a recently established murine model involving injection of adenovirus expressing the TSHR (AdCMVTSHR). Coinjection with adenovirus expressing IL-4 (AdRGDCMVIL-4) decreased the ratio of Th1/Th2-type anti-TSHR Ab subclasses (IgG2a/IgG1) and suppressed the production of IFN-γ by splenocytes in response to TSHR Ag. Importantly, immune deviation toward Th2 was accompanied by significant inhibition of thyroid-stimulating Ab production and reduction in hyperthyroidism. However, in a therapeutic setting, injection of AdRGDCMVIL-4 alone or in combination with AdCMVTSHR into hyperthyroid mice had no beneficial effect. In contrast, coinjection of adenoviruses expressing IL-12 and the TSHR promoted the differentiation of Th1-type anti-TSHR immune responses as demonstrated by augmented Ag-specific IFN-γ secretion from splenocytes without changing disease incidence. Coinjection of adenoviral vectors expressing IL-4 or IL-12 had no effect on the titers of anti-TSHR Abs determined by ELISA or thyroid-stimulating hormone-binding inhibiting Ig assays, suggesting that Ab quality, not quantity, is responsible for disease induction. Our observations demonstrate the critical role of Th1 immune responses in a murine model of Graves’ hyperthyroidism. These data may raise a cautionary note for therapeutic strategies aimed at reversing Th2-mediated autoimmune responses in Graves’ disease in humans.

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“…Disease progression may be controlled by altering the relative levels of cytokines that are required for healing and those that exacerbate infection (8,10,24,25). That the balance between Th1 and Th2 cytokines, rather than the absolute values, is important for disease amelioration has been shown in a model of leishmaniasis (20).…”

Section: Discussionmentioning

confidence: 99%

Interleukin-12 Neutralization Alters Lung Inflammation and Leukocyte Expression of CD80, CD86, and Major Histocompatibility Complex Class II in Mice Infected withHistoplasma capsulatum

Cain

Deepe

2000

Infect Immun

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Histoplasma capsulatum induces a cell-mediated immune response in lungs and lymphoid organs of mammals. Resolution of primary infection in mice depends on interleukin-12 (IL-12), since neutralization of this monokine increases susceptibility to infection. The present study was designed to determine if blockade of IL-12 disrupts the protective immune response by altering the influx of lineage-specific cells into infected lungs and the numbers of cells expressing CD80, CD86, CD119, and major histocompatibility complex class II (MHC II) molecules. In mice given anti-IL-12, there was a 2.5-fold decrease in total numbers of T cells on days 3 to 10 of infection and a 4-fold increase in Mac-1/Gr-1 ؉ cells on days 7 and 10 compared to infected controls. CD80؉ lung cells from anti-IL-12-treated mice were 2-to 3-fold greater than those from controls on days 7 and 10, whereas the total numbers of CD86 ؉ cells were 2-to 3-fold less and MHC II ؉ cells were 1.5-to 2-fold less on days 3 and 5. Cells expressing CD119 were reduced 1.5-fold on day 5. Treatment with monoclonal antibodies (MAb) to CD80, CD86, or both reduced the fungal burden slightly compared to that in rat immunoglobulin G-treated controls, whereas after IL-12 neutralization, blocking of CD80 reduced the tissue burden by 2.5-fold and this correlated with a decrease in IL-4. Regardless, mortality was not altered by treatment with MAb to CD80 or CD86. We conclude that (i) IL-12 neutralization alters the nature of the inflammatory response in lungs and the expression of CD80 and CD86 on lineage-specific cells, (ii) the immune response during infection with H. capsulatum is controlled via mechanisms independent of the CD80 and CD86 costimulatory pathways, and (iii) decreased expression of CD86 and MHC II may modulate generation of optimal protective immunity.Histoplasma capsulatum is an intracellular pathogenic fungus that is responsible for mild disease in immunocompetent hosts and a progressive and fatal disease if untreated in immunocompromised hosts (7). The initial site of infection is the lung, where yeast cells, produced from inhaled microconidia, are ingested by alveolar macrophages (M) via an interaction between the CD11/CD18 family of adhesion molecules and yeast cell wall components (4). Phagocytosis of yeast cells by M results in a permissive environment for survival and replication of yeasts. Resistance to H. capsulatum infection in mammals is primarily dependent on a cellular immune response mediated by T cells and phagocytes. Resolution of infection in mice requires the production of cytokines, especially gamma interferon (IFN-␥) (1,30,33), and release of this cytokine by NK and T cells is dependent on the pathogeninduced release of the monokine interleukin-12 (IL-12) (26). H. capsulatum infection of mice with a genetic absence of IFN-␥ or those given antibodies (Ab) to IL-12 results in an uncontrollable and fatal fungal burden (1, 2, 33). IL-12 release is necessary for M to kill yeasts before day 5 of infection, since animals depleted of IL-12 beyond ...

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Interleukin‐4 and ‐10 exacerbate candidiasis in mice

Cited by 119 publications

References 42 publications

Growth of Candida albicans Cells on the Physiologically Relevant Carbon Source Lactate Affects Their Recognition and Phagocytosis by Immune Cells

Growth of Candida albicans Cells on the Physiologically Relevant Carbon Source Lactate Affects Their Recognition and Phagocytosis by Immune Cells

Prevention of Autoantibody-Mediated Graves’-Like Hyperthyroidism in Mice with IL-4, a Th2 Cytokine

Interleukin-12 Neutralization Alters Lung Inflammation and Leukocyte Expression of CD80, CD86, and Major Histocompatibility Complex Class II in Mice Infected withHistoplasma capsulatum

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