IL-4 and IL-13 regulate the induction of indoleamine 2,3-dioxygenase activity and the control ofToxoplasma gondii replication in human fibroblasts activated with IFN-γ

Chaves, A. S.; Cerávolo, Isabela P.; Gomes, Juliana de Assis Silva; Zani, Carlos L.; Romanha, Álvaro J.; Gazzinelli, Ricardo T.

doi:10.1002/1521-4141(200102)31:2<333::aid-immu333>3.0.co;2-x

Cited by 71 publications

(47 citation statements)

References 60 publications

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“…In the context of our study, IL-13 production by infected DCs may contribute to the development of nonprotective anti-chlamydial immunity by suppressing macrophage function. IL-13 is known to inhibit macrophage production of NO (52-54), IFN-␥-induced tryptophan degradation (55), and production of inflammatory cytokines, such as IL-1 (53,56,57). These are all important mechanisms for the resolution of chlamydial infection.…”

Section: Discussionmentioning

confidence: 99%

Chlamydia muridarum Infection Subverts Dendritic Cell Function to Promote Th2 Immunity and Airways Hyperreactivity

Kaiko

Phipps

Hickey

et al. 2008

The Journal of Immunology

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There is strong epidemiological evidence that Chlamydia infection can lead to exacerbation of asthma. However, the mechanism(s) whereby chlamydial infection, which normally elicits a strong Th type 1 (Th1) immune response, can exacerbate asthma, a disease characterized by dominant Th type 2 (Th2) immune responses, remains unclear. In the present study, we show that Chlamydia muridarum infection of murine bone marrow-derived dendritic cells (BMDC) modulates the phenotype, cytokine secretion profile, and Ag-presenting capability of these BMDC. Chlamydia-infected BMDC express lower levels of CD80 and increased CD86 compared with noninfected BMDC. When infected with Chlamydia, BMDC secrete increased TNF-α, IL-6, IL-10, IL-12, and IL-13. OVA peptide-pulsed infected BMDC induced significant proliferation of transgenic CD4+ DO11.10 (D10) T cells, strongly inhibited IFN-γ secretion by D10 cells, and promoted a Th2 phenotype. Intratracheal transfer of infected, but not control noninfected, OVA peptide-pulsed BMDC to naive BALB/c mice, which had been i.v. infused with naive D10 T cells, resulted in increased levels of IL-10 and IL-13 in bronchoalveolar lavage fluid. Recipients of these infected BMDC showed significant increases in airways resistance and decreased airways compliance compared with mice that had received noninfected BMDC, indicative of the development of airways hyperreactivity. Collectively, these data suggest that Chlamydia infection of DCs allows the pathogen to deviate the induced immune response from a protective Th1 to a nonprotective Th2 response that could permit ongoing chronic infection. In the setting of allergic airways inflammation, this infection may then contribute to exacerbation of the asthmatic phenotype.

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Section: Discussionmentioning

confidence: 99%

Chlamydia muridarum Infection Subverts Dendritic Cell Function to Promote Th2 Immunity and Airways Hyperreactivity

Kaiko

Phipps

Hickey

et al. 2008

The Journal of Immunology

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“…The results from the present study in mouse microglia are consistent with previous reports showing that the expression of IDO and WRS is upregulated by IFN-γ. However, many have reported that IL-4 and IL-13 antagonize the effects of IFN-γ (Chaves et al 2001;Doherty et al 1993;Musso et al 1994;O'Keefe et al 1999;Oswald et al 1992;Yuan et al 1998). In distinct contrast, here we show for the first time that in microglia, IL-4 and IL-13 modulate the expression of these enzymes in a distinct fashion (summarized in Figure 9A, B).…”

Section: Discussionmentioning

confidence: 99%

“…The antagonistic effects of various cytokines to IFN-γ on IDO expression in fibroblasts as well as the myeloid lineage dendritic cells and monocytes have been reported (Chaves et al 2001;Doherty et al 1993;Musso et al 1994;Yuan et al 1998). However, the effects of antiinflammatory cytokines such as IL-4 and IL-13 on the expression of IFN-γ induced IDO and WRS expression in primary microglia, the resident myeloid cells of the CNS that are involved in various pathological disorders of the brain, have not been previously evaluated.…”

Section: Discussionmentioning

confidence: 99%

“…Parallel induction of IDO and WRS by IFN-γ has been found in a number of cell types (Boasso et al 2005); Fleckner et al 1995;Rubin et al 1991Yoshida et al 1981. On the other hand, antiinflammatory cytokines can antagonize many cellular responses induced by IFN-γ, including IDO induction (Chaves et al 2001;Doherty et al 1993;Musso et al 1994;Oswald et al 1992;Yuan et al 1998), but the effects on WRS are not as well studied.…”

Section: Introductionmentioning

confidence: 99%

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IFN‐γ‐induced IDO and WRS expression in microglia is differentially regulated by IL‐4

Yadav

Burudi

Alirezaei

et al. 2007

Glia

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Indoleamine 2,3-dioxygenase (IDO), a tryptophan catabolizing enzyme, has been implicated in the pathogenesis of various neurological disorders. IDO expression is induced by IFN-γ and leads to neurotoxicity by generating quinolinic acid. Additionally, it inhibits the immune response through both tryptophan depletion and generating other tryptophan catabolites. IL-4 and IL-13 have been shown to control IDO expression by antagonizing the effects of IFN-γ in different cell types. Here, we investigated the effects of these cytokines on IDO expression in microglia. Interestingly, we observed that both IL-4 and IL-13 greatly enhanced IFN-γ induced IDO expression. However, tryptophanyl-tRNA synthetase (WRS), which is coinduced with IDO by IFN-γ, is downregulated by IL-4 and IL-13. The effect of IL-4 and IL-13 was independent of STAT-6. Modulation of IDO but not WRS was eliminated by inhibition of protein phosphatase 2A (PP2A) activity. The phosphatidylinositol 3-kinase (PI3K) pathway further differentiated the regulation of these two enzymes, as inhibiting the PI3K pathway eliminated IFN-γ induction of IDO, whereas such inhibition greatly enhanced WRS expression. These findings show discordance between modulations of expression of two distinct enzymes utilizing tryptophan as a common substrate, and raise the possibility of their involvement in regulating immune responses in various neurological disorders.

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“…Previous studies have indicated that the production of Th2 cytokines such as IL-4 and IL-10 may be a contributory factor leading to death in the acute phase of T. gondii infection (2,18). One of the suppressor mechanisms of B-2 cells from T. gondii-infected UIR GKO mice (11) and UIR WT B6 mice (Fig.…”

mentioning

confidence: 99%

A Novel B‐2 Suppressor Cell Regulating Susceptibility/Resistance of Mice to Toxoplasma gondii Infection

Mun

Aosai

Fang

et al. 2005

Microbiology and Immunology

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Irradiation treatment enhanced resistance of C57BL/6, but not BALB/c against Toxoplasma gondii infection. Six Gy‐irradiated (IR) C57BL/6 recipients of B‐2 cells from T. gondii‐infected C57BL/6 died after infection. B‐2 suppressor cells from infected C57BL/6 enhanced production of IL‐4 and IL‐10 in peritoneal exudate cells (PECs), and down‐regulated NO release in peritoneal macrophages after infection. On the other hand, B‐2 suppressor cells were not detected in a strain, BALB/c, resistant against infection. These data indicated that irradiation‐sensitive B‐2 cells regulated susceptibility/resistance in mice against T. gondii infection.

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IL-4 and IL-13 regulate the induction of indoleamine 2,3-dioxygenase activity and the control ofToxoplasma gondii replication in human fibroblasts activated with IFN-γ

Cited by 71 publications

References 60 publications

Chlamydia muridarum Infection Subverts Dendritic Cell Function to Promote Th2 Immunity and Airways Hyperreactivity

Chlamydia muridarum Infection Subverts Dendritic Cell Function to Promote Th2 Immunity and Airways Hyperreactivity

IFN‐γ‐induced IDO and WRS expression in microglia is differentially regulated by IL‐4

A Novel B‐2 Suppressor Cell Regulating Susceptibility/Resistance of Mice to Toxoplasma gondii Infection

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