A Role for Caspases in Controlling IL-4 Expression in T Cells

Sehra, Sarita; Patel, Dipak R.; Kusam, Saritha; Wang, Zheng Yu; Chang, Cheong Hee; Dent, Alexander L.

doi:10.4049/jimmunol.174.6.3440

Cited by 17 publications

(15 citation statements)

References 47 publications

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“…An alternative but not mutually exclusive interpretation is that caspase inhibitors modulate Th2 cytokine production. Thus, the caspase inhibitor Z-VAD-FMK augments IL-4 production by primary but not Th2-committed T cells (69). In this regard, levels of IFN-γ, IL-4, and IL-10 in lung homogenates of uninfected mice administered Boc-D-FMK or suramin for 7 days did not differ from those of mice given either Z-FA-FMK or PBS (data not shown).…”

Section: Figurementioning

confidence: 82%

Apoptosis modulates protective immunity to the pathogenic fungus Histoplasma capsulatum

Allen

Deepe²

2005

Journal of Clinical Investigation

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Pathogen-induced apoptosis of lymphocytes is associated with increased susceptibility to infection. In this study, we determined whether apoptosis influenced host resistance to the fungus Histoplasma capsulatum. The level of apoptotic leukocytes progressively increased in the lungs of naive and immune mice during the course of H. capsulatum infection. T cells constituted the dominant apoptotic population. Apoptosis was diminished in H. capsulatum-infected gld/gld and TNF-α-deficient mice; concomitantly, the fungal burden exceeded that of controls. Treatment of naive and H. capsulatum-immune mice with caspase inhibitors decreased apoptosis but markedly enhanced the severity of infection. Administration of a proapoptotic dose of suramin diminished the fungal burden. The increased burden in recipients of a caspase inhibitor was associated with elevations in IL-4 and IL-10 levels. In the absence of either of these cytokines, caspase inhibition suppressed apoptosis but did not increase the fungal burden. Thus, apoptosis is a critical element of protective immunity to H. capsulatum. Production of IL-4 and IL-10 is markedly elevated when apoptosis is inhibited, and the release of these cytokines exacerbates the severity of infection.

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Section: Figurementioning

confidence: 82%

Apoptosis modulates protective immunity to the pathogenic fungus Histoplasma capsulatum

Allen

Deepe²

2005

Journal of Clinical Investigation

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“…This is in agreement with previous data analyses that appear to associate Th2 proliferation with altered regulation of apoptosis. [2][3][4][5][6] Lymphocyte death was associated with several genes of the TNF ligand and receptor superfamilies, most notably TNF, FAS, TNFRSF4, TNFRSF25, TNFRSF1B and TNFS7. These genes are involved in regulating T-cell apoptosis and proliferation.…”

Section: Discussionmentioning

confidence: 99%

“…[1][2][3][4][5][6][7] Supernatants from 11 patients and five controls were studied. In supernatants from patients, IL-5 was significantly higher in supernatants from allergen-challenged PBMC, 100 (0-500) vs 0 (0-0), Po0.01, as was IL-13, 13 (0-270) vs 0 (0-0), Po0.05.…”

Section: Proliferation Of Th2 Cells Following Allergen Stimulationmentioning

confidence: 99%

“…The differentiation of Th cells is determined by a complex interplay between multiple factors such as antigen type and dose, dendritic cells, the T-cell receptor, co-stimulatory signals and the cytokine microenvironment as well as apoptotic regulators. [1][2][3][4][5][6][7] DNA microarray studies have described hundreds of differentially expressed genes in CD4 þ T cells stimulated by cytokines, 8,9 taken from transgenic mice, 10 or from peripheral blood of patients with atopic dermatitis. 11 These findings indicate that the proliferation of Th2 cells depends on multiple, interacting genes.…”

Section: Introductionmentioning

confidence: 99%

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A network-based analysis of allergen-challenged CD4+ T cells from patients with allergic rhinitis

Benson

Carlsson²,

Guillot

et al. 2006

Genes Immun

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We performed a network-based analysis of DNA microarray data from allergen-challenged CD4 þ T cells from patients with seasonal allergic rhinitis. Differentially expressed genes were organized into a functionally annotated network using the Ingenuity Knowledge Database, which is based on manual review of more than 200 000 publications. The main function of this network is the regulation of lymphocyte apoptosis, a role associated with several genes of the tuber necrosis factor superfamily. The expression of TNFRSF4, one of the genes in this family, was found to be 48 times higher in allergen-challenged cells than in diluent-challenged cells. TNFRSF4 is known to inhibit apoptosis and to enhance Th2 proliferation. Examination of a different material of allergen-stimulated peripheral blood mononuclear cells showed a higher number of interleukin-4 þ type 2 CD4 þ T (Th2) cells in patients than in controls (Po0.01), as well as a higher number of non-apoptotic Th2 cells in patients (Po0.01). The number of Th2 cells expressing TNFRSF4, TNFSF7 and TNFRSF1B was also significantly higher in patients. Treatment with anti-TNFSF4 resulted in a significantly decreased number of Th2 cells (Po0.05). A logical inference from all this is that the proliferation of allergen-challenged Th2 cells is associated with a decreased apoptosis of Th2 cells and an increase in TNFRSF4 signalling.

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“…27). Caspases also regulate T helper cell differentiation because their inhibition leads to increased IL-4 production and therefore enhanced Th2 polarization of CD4 ϩ T cells (28). In addition, when naïve T cells are co-stimulated with anti-Fas antibody during initial activation, they show increased production of Th1 type cytokine interferon-␥ (29).…”

mentioning

confidence: 99%

Interleukin-4 Inhibits Caspase-3 by Regulating Several Proteins in the Fas Pathway during Initial Stages of Human T Helper 2 Cell Differentiation

Granberg

Marttila

Nyman

et al. 2007

Molecular & Cellular Proteomics

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Interleukin-4 (IL-4) is the main cytokine that polarizes activated naïve CD4؉ T cells in the T helper 2 (Th2) direction. IL-4 also regulates the subsequent stages of Th2 cellmediated diseases, such as allergies. We conducted a proteomics study to identify IL-4-induced differences during the initial stages of T helper cell differentiation. Primary CD4؉ T lymphocytes were isolated from human cord blood, activated through CD3 and CD28, and cultured in the presence or absence of IL-4. Soluble proteins were separated by two-dimensional electrophoresis and visualized by staining with autoradiography, which indicated that at least 20 proteins might be regulated by IL-4. From this minimum of 20 stained proteins, altogether 35 proteins were identified using tandem mass spectrometry. Interestingly the fragmented form of GDP dissociation inhibitor expressed in lymphocytes/Rho GDP dissociation inhibitor 2 (Ly-GDI), a known target of Caspase-3, was observed to be downregulated in IL-4-treated cells. It was shown in further studies that IL-4 decreases Caspase-3 activity and cell death in these cells. Neutralizing Fas-Fas ligand interaction led to decreased Caspase-3 activity and lowered Ly-GDI fragmentation. We further characterized the effects of IL-4 on the expression of main regulators in the Fas-mediated pathway. We demonstrated that IL-4 decreases expression of Fas receptor and increases expression of Bid, Bcl-2, and Bcl-xL. Importantly IL-4 significantly up-regulated the short form of c-FLIP, although the levels of c-FLIP long were unaltered after IL-4 induction. Taken together, our results indicate that IL-4 inhibits caspase activity during the initial stages of human Th2 cell differentiation by regulating expression of several key players in the Fas-induced pathway.

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A Role for Caspases in Controlling IL-4 Expression in T Cells

Cited by 17 publications

References 47 publications

Apoptosis modulates protective immunity to the pathogenic fungus Histoplasma capsulatum

Apoptosis modulates protective immunity to the pathogenic fungus Histoplasma capsulatum

A network-based analysis of allergen-challenged CD4+ T cells from patients with allergic rhinitis

Interleukin-4 Inhibits Caspase-3 by Regulating Several Proteins in the Fas Pathway during Initial Stages of Human T Helper 2 Cell Differentiation

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