Inhibitory Effect of the 4-Aminotetrahydroquinoline Derivatives, Selective Chemoattractant Receptor-Homologous Molecule Expressed on T Helper 2 Cell Antagonists, on Eosinophil Migration Induced by Prostaglandin D2

The type-III interferon (IFN) family is composed of 3 molecules in humans: IFN-λ1 (interleukin-29 [IL-29]), IFN-λ2 (IL-28A), and IFN-λ3 (IL-28B), each of which signals through the same receptor complex. Plasmacytoid dendritic cells (pDCs) are major IFN-λ producers among peripheral lymphocytes. Recently, it has been shown that IFN-λ1 exerts a powerful inhibitory effect over the T-helper 2 (Th2) response by antagonizing the effect of IL-4 on CD4+ T cells and inhibiting the production of Th2-associated cytokines. Here, we asked whether Th2 cytokines exert reciprocal control over IFN-λ production. IL-4 treatment during stimulation of human peripheral lymphocytes significantly elevated IFN-λ1 transcription and secretion. However, pDCs were not directly responsive to IL-4. Using depletion and reconstitution experiments, we showed that IL-4–responsive monocytes are an intermediary cell, responding to IL-4 by elevating their secretion of IL-1 receptor antagonist (IL-Ra); this IL-1Ra acts on pDCs to elevate their IFN-λ1 output. Thus, our experiments revealed a novel mechanism for regulation of both IFN-λ1 production and pDC function, and suggests an expanded immunomodulatory role for Th2-associated cytokines.

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Selective disruption of interleukin 4 autocrine-regulated loop by a tyrosine kinase inhibitor restricts activity of T-helper 2 cells

Blood ◽

10.1182/blood.v95.12.3816.012k29_3816_3822 ◽

2000 ◽

Vol 95 (12) ◽

pp. 3816-3822 ◽

Cited By ~ 2

Author(s):

Li Hua Wang ◽

Robert A. Kirken ◽

Xiao Yi Yang ◽

Rebecca A. Erwin ◽

Luis DaSilva ◽

...

Keyword(s):

Tyrosine Kinase ◽

Cell Line ◽

Kinase Inhibitors ◽

Kinase Inhibitor ◽

Inhibitory Effect ◽

Interleukin 4 ◽

Th2 Cells ◽

T Helper ◽

Th1 Cell ◽

T Helper 2

Interleukin (IL) 4 is a potent immunomodulatory cytokine secreted by T-helper 2 (Th2) cells and Th2 mast cells that promotes the commitment of cells. However, unregulated production and release of IL-4 can exacerbate allergic reactions and increase susceptibility to infectious organisms and viruses. Here, we present evidence that AG-490, a Janus tyrosine kinase (JAK) 2-JAK3 inhibitor, effectively blocked IL-4 gene expression and secretion in the Th2 cell line D10 that was not occurring after anti-CD3 antibody stimulation, whereas AG-490 had no inhibitory effect on production of other Th2 cytokines or cytokines synthesized by the corresponding Th1 cell line clone 29. AG-490 potently inhibited IL-4–mediated proliferation of both D10 and the IL-4–dependent cell line CT.4S. Moreover, AG-490 markedly inhibited IL-4 activation of JAK3 and blocked the downstream activation of signal transducer and activator of transcription 6, as judged by tyrosine phosphorylation, DNA binding, and transcription assays. In contrast, AG-490 did not affect tumor necrosis factor  activation of NF-κB at similar concentrations of drug. These data suggest that tyrosine kinase inhibitors that inhibit JAK3 may have previously unrecognized and selective clinical potential as immunotherapeutic drugs to treat Th2-mediated diseases driven by IL-4.

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Activation of the D prostanoid 1 receptor suppresses asthma by modulation of lung dendritic cell function and induction of regulatory T cells

Journal of Experimental Medicine ◽

10.1084/jem.20061196 ◽

2007 ◽

Vol 204 (2) ◽

pp. 357-367 ◽

Cited By ~ 145

Author(s):

Hamida Hammad ◽

Mirjam Kool ◽

Thomas Soullié ◽

Shuh Narumiya ◽

François Trottein ◽

...

Keyword(s):

T Cells ◽

Regulatory T Cells ◽

Airway Inflammation ◽

Cell Function ◽

Interleukin 10 ◽

Prostaglandin D2 ◽

T Helper ◽

T Helper 2 ◽

Novel Treatments ◽

Dependent Protein

Prostaglandins (PGs) can enhance or suppress inflammation by acting on different receptors expressed by hematopoietic and nonhematopoietic cells. Prostaglandin D2 binds to the D prostanoid (DP)1 and DP2 receptor and is seen as a critical mediator of asthma causing vasodilation, bronchoconstriction, and inflammatory cell influx. Here we show that inhalation of a selective DP1 agonist suppresses the cardinal features of asthma by targeting the function of lung dendritic cells (DCs). In mice treated with DP1 agonist or receiving DP1 agonist-treated DCs, there was an increase in Foxp3+ CD4+ regulatory T cells that suppressed inflammation in an interleukin 10–dependent way. These effects of DP1 agonist on DCs were mediated by cyclic AMP–dependent protein kinase A. We furthermore show that activation of DP1 by an endogenous ligand inhibits airway inflammation as chimeric mice with selective hematopoietic loss of DP1 had strongly enhanced airway inflammation and antigen-pulsed DCs lacking DP1 were better at inducing airway T helper 2 responses in the lung. Triggering DP1 on DCs is an important mechanism to induce regulatory T cells and to control the extent of airway inflammation. This pathway could be exploited to design novel treatments for asthma.

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Accumulation of CRTH2-positive T-helper 2 and T-cytotoxic 2 cells at implantation sites of human decidua in a prostaglandin D2-mediated manner

MHR Basic science of reproductive medicine ◽

10.1093/molehr/8.2.181 ◽

2002 ◽

Vol 8 (2) ◽

pp. 181-187 ◽

Cited By ~ 58

Author(s):

T. Michimata

Keyword(s):

Prostaglandin D2 ◽

T Helper ◽

T Helper 2 ◽

Implantation Sites ◽

Human Decidua

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Selective disruption of interleukin 4 autocrine-regulated loop by a tyrosine kinase inhibitor restricts activity of T-helper 2 cells

Blood ◽

10.1182/blood.v95.12.3816 ◽

2000 ◽

Vol 95 (12) ◽

pp. 3816-3822 ◽

Cited By ~ 12

Author(s):

Li Hua Wang ◽

Robert A. Kirken ◽

Xiao Yi Yang ◽

Rebecca A. Erwin ◽

Luis DaSilva ◽

...

Keyword(s):

Tyrosine Kinase ◽

Cell Line ◽

Kinase Inhibitors ◽

Kinase Inhibitor ◽

Inhibitory Effect ◽

Interleukin 4 ◽

Th2 Cells ◽

T Helper ◽

Th1 Cell ◽

T Helper 2

Abstract Interleukin (IL) 4 is a potent immunomodulatory cytokine secreted by T-helper 2 (Th2) cells and Th2 mast cells that promotes the commitment of cells. However, unregulated production and release of IL-4 can exacerbate allergic reactions and increase susceptibility to infectious organisms and viruses. Here, we present evidence that AG-490, a Janus tyrosine kinase (JAK) 2-JAK3 inhibitor, effectively blocked IL-4 gene expression and secretion in the Th2 cell line D10 that was not occurring after anti-CD3 antibody stimulation, whereas AG-490 had no inhibitory effect on production of other Th2 cytokines or cytokines synthesized by the corresponding Th1 cell line clone 29. AG-490 potently inhibited IL-4–mediated proliferation of both D10 and the IL-4–dependent cell line CT.4S. Moreover, AG-490 markedly inhibited IL-4 activation of JAK3 and blocked the downstream activation of signal transducer and activator of transcription 6, as judged by tyrosine phosphorylation, DNA binding, and transcription assays. In contrast, AG-490 did not affect tumor necrosis factor  activation of NF-κB at similar concentrations of drug. These data suggest that tyrosine kinase inhibitors that inhibit JAK3 may have previously unrecognized and selective clinical potential as immunotherapeutic drugs to treat Th2-mediated diseases driven by IL-4.

Download Full-text