A critical role of IL-2 for the production and gene transcription of IL-5 in allergen-specific human T cell clones

Mori, Akio; Suko, Matsunobu; Kaminuma, Osamu; Nishizaki, Yoko; Mikami, Tadashi; Ohmura, Takafumi; Hoshino, Akihiko; Inoue, Satoshi; Tsuruoka, Nobuo; Okumura, Yasushi; Satô, Gen P.; Itō, Kōji; Okudaira, Hirokazu

doi:10.1093/intimm/8.12.1889

Cited by 30 publications

(37 citation statements)

References 44 publications

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“…Plasmid cons tructs PIL-5(-5 1 1)Luc, a human IL-5 promoter/enhancer (-5 1 1 to +4 relative to the transcription initiation site)-luciferase gene construct, was prepared as described previously (35). The reporter constructs (3xCLE0-tk-Luc, 3xCLE0mt6-tk-Luc, and 3xCLE0mt7-tk-Luc) were generated by cloning three copies of the corresponding oligonucleotides as direct repeats into the Xho I and Hind III sites of the pGL3-tk vector, which carries the truncated thymidine kinase (tk) promoter connected to the luciferase reporter gene.…”

Section: Subjectsmentioning

confidence: 99%

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Transcriptional Regulation of IL-5 Gene by Nontransformed Human T Cells Through the Proximal Promoter Element.

et al. 2000

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Objective IL-5 is strongly involved in the eosinophilic inflammation in bronchial asthma and atopic dermatitis. Wehave previously reported that IL-5 synthesis in atopic and nonatopic asthmatics is significantly enhanced compared to control subjects. T cell IL-5 synthesis is regulated through several transcriptional elements, one of which is the proximal human IL-5 promoter (-62 to -46). The present study was undertaken to delineate the transcriptional regulation through this element using nontransformed human T cells. Methods Con A blast lymphocytes which tolerate electroporation were derived from peripheral blood lymphocytes. Luciferase reporter analysis and gel shift analysis were performed. Results The proximal promoter element is the overlapping binding site for the constitutive binding factor, Oct-1, and the inducible one, AP-1. The transcriptional induction was ascribed to the inducible binding, while the constitutive binding was rather inhibitory. A mutant element which lost the constitutive binding but retained the inducible binding exerted 3 times more transcriptional activity compared to the wild type element. In contrast, another mutant element which lost the inducible binding and retained the constitutive binding exhibited no transcriptional induction. Gel shift analysis clarified that the inducible binding was more prominent and the constitutive binding was less in IL-5-producing T cells derived from asthma patients compared to IL-5-nonproducing cells derived from control subjects. Conclusions The ratio of the inducible/constitutive binding to the proximal promoter element maydetermine the capacity of human Th cells to transcribe IL-5 gene, and its regulation may control eosinophilic inflammation. (Internal Medicine 39: 618-625, 2000)

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Section: Subjectsmentioning

confidence: 99%

“…Protein extracts were then prepared and luciferase activity was assayed using the Luciferase Assay System (Promega). p-Galactosidase activity was assayed using chlorophenol red-P-D-galactopyranoside (CPRG) as the substrate, as described previously (35).…”

Section: Subjectsmentioning

confidence: 99%

Transcriptional Regulation of IL-5 Gene by Nontransformed Human T Cells Through the Proximal Promoter Element.

et al. 2000

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“…In addition, an inverse effect is found in the presence of neutralizing anti-IL-2 antibody, indicating that endogenously produced IL-2 determines the ultimate effect of cAMP-elevating agents. The production of IL-5 is known to be dependent on the IL-2 levels [22], and IL-2 production is inhibited by cAMP [14]. Yet, our results indicate that the inhibition of IL-5 by cAMP is not a consequence of reduced IL-2 levels, but due to a direct effect involving a cross-talk between IL-2 and cAMP-dependent signaling.…”

Section: Discussionmentioning

confidence: 49%

Sensitivity of IL‐5 production to the cAMP‐dependent pathway in human T cells is reduced by exogenous IL‐2 in a phosphoinositide 3‐kinase‐dependent way

Heijink¹,

Kauffman²,

Postma³

et al. 2003

Eur J Immunol

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The cAMP-dependent pathway plays an important role in the regulation of T cell-mediated immune responses by inhibition of T cell proliferation, activation and production of Th1-like cytokines. Depending on costimulatory signals and on the activation status of T cells, cAMP also regulates the production of Th2-like cytokines, yet the mechanism is not completely defined. We investigated the effect of costimulation with IL-2 on cAMP-mediated inhibition of IL-5 secretion and the signaling pathways involved in these effects in freshly isolated, § -CD3/ § -CD28-stimulated human T lymphocytes. We demonstrate that IL-2 counteracts the cAMP-mediated inhibitory effects on IL-5 secretion by the modulation of phosphoinositide 3-kinase (PI3-K)-dependent signaling. Our results indicate that phosphorylation of cAMPresponsive element-binding protein (CREB) and the activity of the small GTPase Rap1 are unlikely involved in the protective effect of IL-2. Instead, the effect of IL-2 may be mediated by the PI3-K-dependent inactivation of the forkhead-related transcription factor FKHR-L1, down-regulation of p27 kip and abrogation of the cAMP-mediated inhibition of activator protein (AP)-1 binding activity. Together, our results indicate that increased IL-2-dependent PI3-K signaling leads to impaired negative feedback control of the production of Th2-type cytokine IL-5 by the cAMP-dependent pathway.

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“…There were increased numbers of bronchoalveolar lavage cells expressing mRNA for IL-2 and IL-4 in the CR group, suggesting a primary defect of cytokine regulation in these patients. The presence of TH 2 cytokines has the potential of augmenting AP-1 expression (14,15), which in turn can switch on the production of the same class of cytokines (16, 17), leading to a proinflammatory amplification loop. Irrespective of whether enhanced expression of AP-1 is primary or secondary, the net result is an excessive accumulation of this critical transcription factor.…”

Section: Discussionmentioning

confidence: 99%

“…The most abundant AP-1 heterodimer is c-Fos:c-Jun, and c-Fos expression is thereby the inducible marker of the most transcriptionally active AP-1 complex. AP-1 activates the IL-4, IL-5, and GM-CSF genes, which are important in asthma pathogenesis (14,15). In addition, IL-5 and GM-CSF activate c-fos transcription and may provide one mechanism perpetuating the asthmatic inflammatory process (16,17).…”

Section: Introductionmentioning

confidence: 99%

Corticosteroid-resistant bronchial asthma is associated with increased c-fos expression in monocytes and T lymphocytes.

Lane¹,

Adcock²,

Richards³

et al. 1998

J. Clin. Invest.

134

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Unstimulated peripheral blood mononuclear cells (PBMCs) from corticosteroid-resistant (CR) but not corticosteroidsensitive (CS) asthmatics demonstrate increased activating peptide-1 (AP-1)-and decreased glucocorticoid receptor (GR)-DNA binding. We test whether these abnormalities are associated with excessive generation of c-fos , the inducible component of AP-1. The c-fos transcription rate, mRNA and protein levels, and GR-DNA binding were quantitated in PBMCs, T cells, and monocytes from CS, CR, and nonasthmatic subjects. There was a 1.7-, 4.2-, and 2.3-fold greater increase in the baseline c-fos transcription rate, mRNA expression, and protein levels, respectively, in PBMCs derived from CR compared with CS patients. At optimal stimulation with PMA, there was a 5.7-, 3.4-, and 2-fold greater increase in the c-fos transcription rate, mRNA accumulation, and protein levels, respectively, in CR compared with CS PBMCs. These abnormalities were detected in both the T cell and monocyte subpopulations. PMA stimulation converted PBMCs from a CS to a CR phenotype and was associated with direct interaction between c-Fos and the GR. Pretreatment of PBMCs from CR patients with c-fos antisense oligonucleotides enhanced GR-DNA binding activity in CR PBMCs stimulated with dexamethasone. We suggest that increased c-fos synthesis provides a major mechanism for the increased AP-1-and decreased GR-DNA binding seen in CR asthma. ( J. Clin. Invest. 1998. 102 : 2156-2164.)

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A critical role of IL-2 for the production and gene transcription of IL-5 in allergen-specific human T cell clones

Cited by 30 publications

References 44 publications

Transcriptional Regulation of IL-5 Gene by Nontransformed Human T Cells Through the Proximal Promoter Element.

Transcriptional Regulation of IL-5 Gene by Nontransformed Human T Cells Through the Proximal Promoter Element.

Sensitivity of IL‐5 production to the cAMP‐dependent pathway in human T cells is reduced by exogenous IL‐2 in a phosphoinositide 3‐kinase‐dependent way

Corticosteroid-resistant bronchial asthma is associated with increased c-fos expression in monocytes and T lymphocytes.

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