Manganese promotes phorbol ester-induced interleukin-2 production via AP-1 activation in Jurkat T-cells

We have characterized the regulation of nuclear factors involved in transcriptional control of the interleukin-2 (IL-2) promoter-enhancer activity in Jurkat T cells stimulated with superantigen presented on HLA-DR transfectants combined with the ligands LFA-3 (CD58) and B7-1 (CD80). Gel shift analyses showed that NF-AT was strongly induced in LFA-3-costimulated Jurkat T cells, suggesting that NF-AT is a key target nuclear factor for the CD2-LFA-3 pathway. Studies using HLA-DR-B7-1-LFA-3 triple transfectants showed that the LFA-3-induced NF-AT DNA binding activity was negatively regulated by B7-1 costimulation. In contrast, induction of a CD28 response complex containing only c-Rel proteins was seen after B7-1 costimulation. Both LFA-3 costimulation and B7-1 costimulation induced the AP-1 and NF-kappaB nuclear factors. Distinct compositions of the NF-AT complexes were seen in B7-1- and LFA-3-costimulated cells. LFA-3 induced primarily Jun-D, Fra-1, and Fra-2, while B7-1 induced June-D-Fos complexes. In contrast, AP-1 and NF-kappaB complexes induced in B7-1- and LFA-3-costimulated T cells showed similar contents. Transient transfection of Jurkat T cells with a construct encoding the IL-2 enhancer-promoter region (position -500 to +60) linked to a luciferase reporter gene revealed that B7-1 costimulation was required to induce strong transcriptional activity. Combined B7-1-LFA-3 costimulation resulted in a synergistic increase in IL-2 transcriptional activity. Multimers of the AP-1, NF-AT, NF-kappaB, and CD28 response elements showed distinct kinetics and activity after LFA-3 and B7-1 costimulation and revealed that B7-1 and LFA-3 converge to superinduce transcriptional activity of the AP-1, NF-AT, and CD28 response elements. Transcriptional studies with an IL-2 enhancer-promoter carrying a mutation in the CD28 response element site revealed that the activity was reduced by 80% after B7-1 and B7-1-LFA-3 costimulation whereas the transcriptional activity induced by LFA-3 was unaffected. Our data strongly suggest a selectivity in induction of nuclear factors by the CD2-LFA-3 and CD28-B7-1 pathways. This selectivity may contribute to regulation of the levels of IL-2 induced by LFA-3 and B7-1 costimulation and favor autocrine and paracrine T-cell responses, respectively.

Download Full-text

Polysaccharide Isolated from Zizyphus jujuba (紅棗 Hóng Zǎo) Inhibits Interleukin-2 Production in Jurkat T Cells

Journal of Traditional and Complementary Medicine ◽

10.4103/2225-4110.124360 ◽

2014 ◽

Vol 4 (2) ◽

pp. 132-135 ◽

Cited By ~ 6

Author(s):

Bo-Yang Hsu ◽

Yuh-Chi Kuo ◽

Bing-Huei Chen

Keyword(s):

T Cells ◽

Interleukin 2 ◽

Jurkat T Cells ◽

Zizyphus Jujuba

Download Full-text

The AP-1 site at -150 bp, but not the NF-kappa B site, is likely to represent the major target of protein kinase C in the interleukin 2 promoter.

Journal of Experimental Medicine ◽

10.1084/jem.175.3.853 ◽

1992 ◽

Vol 175 (3) ◽

pp. 853-862 ◽

Cited By ~ 42

Author(s):

J Jain ◽

V E Valge-Archer ◽

A J Sinskey ◽

A Rao

Keyword(s):

T Cells ◽

Protein Kinase C ◽

T Cell ◽

Protein Kinase ◽

Phorbol Ester ◽

Interleukin 2 ◽

Prolonged Treatment ◽

Nf Kappa B ◽

Kinase C ◽

T Cell Clone

Stimulation of T cells with antigen results in activation of several kinases, including protein kinase C (PKC), that may mediate the later induction of activation-related genes. We have examined the potential role of PKC in induction of the interleukin 2 (IL-2) gene in T cells stimulated through the T cell receptor/CD3 complex. We have previously shown that prolonged treatment of the untransformed T cell clone Ar-5 with phorbol esters results in downmodulation of the alpha and beta isozymes of PKC, and abrogates induction of IL-2 mRNA and protein. Here we show that phorbol ester treatment also abolishes induction of chloramphenicol acetyltransferase activity in Ar-5 cells transfected with a plasmid containing the IL-2 promoter linked to this reporter gene. The IL-2 promoter contains binding sites for nuclear factors including NFAT-1, Oct, NF-kappa B, and AP-1, which are all potentially sensitive to activation of PKC. We show that induction of a trimer of the NFAT and Oct sites is not sensitive to phorbol ester treatment, and that mutations in the NF-kappa B site have no effect on inducibility of the IL-2 promoter. In contrast, mutations in the AP-1 site located at -150 bp almost completely abrogate induction of the IL-2 promoter, and appearance of an inducible nuclear factor binding to this site is sensitive to PKC depletion. Moreover, cotransfections with c-fos and c-jun expression plasmids markedly enhance induction of the IL-2 promoter in minimally stimulated T cells. Our results indicate that the AP-1 site at -150 bp represents a major, if not the only, site of PKC responsiveness in the IL-2 promoter.

Download Full-text

Loureirin B Exerts its Immunosuppressive Effects by Inhibiting STIM1/Orai1 and KV1.3 Channels

Frontiers in Pharmacology ◽

10.3389/fphar.2021.685092 ◽

2021 ◽

Vol 12 ◽

Author(s):

Shujuan Shi ◽

Qianru Zhao ◽

Caihua Ke ◽

Siru Long ◽

Feng Zhang ◽

...

Keyword(s):

T Cells ◽

Molecular Mechanisms ◽

Cell Model ◽

Interleukin 2 ◽

Immunosuppressive Effect ◽

Dependent Manner ◽

Jurkat T Cells ◽

In The Wild ◽

Resina Draconis ◽

Loureirin B

Loureirin B (LrB) is a constituent extracted from traditional Chinese medicine Resina Draconis. It has broad biological functions and an impressive immunosuppressive effect that has been supported by numerous studies. However, the molecular mechanisms underlying Loureirin B-induced immune suppression are not fully understood. We previously reported that Loureirin B inhibited KV1.3 channel, calcium ion (Ca2+) influx, and interleukin-2 (IL-2) secretion in Jurkat T cells. In this study, we applied CRISPR/Cas9 to edit KV1.3 coding gene KCNA3 and successfully generated a KV1.3 knockout (KO) cell model to determine whether KV1.3 KO was sufficient to block the Loureirin B-induced immunosuppressive effect. Surprisingly, we showed that Loureirin B could still inhibit Ca2+ influx and IL-2 secretion in the Jurkat T cells in the absence of KV1.3 although KO KV1.3 reduced about 50% of Ca2+ influx and 90% IL-2 secretion compared with that in the wild type cells. Further experiments showed that Loureirin B directly inhibited STIM1/Orai1 channel in a dose-dependent manner. Our results suggest that Loureirin B inhibits Ca2+ influx and IL-2 secretion in Jurkat T cells by inhibiting both KV1.3 and STIM1/Orai1 channels. These studies also revealed an additional molecular target for Loureirin B-induced immunosuppressive effect, which makes it a promising leading compound for treating autoimmune diseases.

Download Full-text

Endopeptidase 24.11 (CD10/NEP) is required for phorbol ester‐induced growth arrest in Jurkat T cells

The FASEB Journal ◽

10.1096/fasebj.11.11.9285485 ◽

1997 ◽

Vol 11 (11) ◽

pp. 869-879 ◽

Cited By ~ 22

Author(s):

Bernard Mari ◽

Sandrine Gueren ◽

Laurence Maulon ◽

Nathalie Belhacene ◽

Dariush Farahi Far ◽

...

Keyword(s):

T Cells ◽

Phorbol Ester ◽

Growth Arrest ◽

Jurkat T Cells ◽

Endopeptidase 24.11

Download Full-text

A High-Throughput System for Identifying Human Interleukin-2 Inducers and/or Repressors Based on the Expression of a Reporter Gene in Jurkat T Cells

Analytical Biochemistry ◽

10.1006/abio.2001.5537 ◽

2002 ◽

Vol 303 (2) ◽

pp. 202-206 ◽

Cited By ~ 2

Author(s):

Yeu Su ◽

Hui Ru Li

Keyword(s):

T Cells ◽

Reporter Gene ◽

High Throughput ◽

Interleukin 2 ◽

Jurkat T Cells

Download Full-text

Mild electrical stimulation suppresses interleukin-2 expression in Jurkat T cells

Cytokine ◽

10.1016/j.cyto.2009.07.465 ◽

2009 ◽

Vol 48 (1-2) ◽

pp. 110

Author(s):

Yuichiro Shimauchi ◽

Saori Morino ◽

Shuichiro Yano ◽

Mary Ann Suico ◽

Tsuyoshi Shuto ◽

...

Keyword(s):

T Cells ◽

Electrical Stimulation ◽

Interleukin 2 ◽

Jurkat T Cells

Download Full-text

Anti-allergic and Cytotoxic Effects of Sesquiterpenoids and Phenylpropanoids Isolated from Magnolia biondii

Natural Product Communications ◽

10.1177/1934578x1701201005 ◽

2017 ◽

Vol 12 (10) ◽

pp. 1934578X1701201 ◽

Cited By ~ 1

Author(s):

Thi Tuyet Mai Nguyen ◽

Thi Thu Nguyen ◽

Hyun-Su Lee ◽

Bomi Lee ◽

Byung Sun Min ◽

...

Keyword(s):

T Cells ◽

Optical Rotation ◽

Interleukin 2 ◽

2D Nmr ◽

Inhibitory Effect ◽

2D Nmr Spectroscopy ◽

Jurkat T Cells ◽

Cytotoxic Effects ◽

D 12 ◽

Mcf 7

Ten sesquiterpenoids (1-10) and six phenylpropanoid derivatives (11-16) were isolated from the flower buds of Magnolia biondii Pamp. Their structures were determined by 1D- and 2D-NMR spectroscopy, mass spectrometry, and optical rotation. To evaluate their anti-allergic properties, the inhibitory effect of each isolate (1-16) on interleukin-2 (IL-2) gene expression was examined in Jurkat T cells. Among the isolated compounds, three sesquiterpenoids (2, 5, and 7) and two monoterpenoids (12 and 13) strongly inhibited IL-2 production in Jurkat T cells. Four compounds, (-)-parthenolide (2), eudesm-4(15)-eno-1β,6α-diol (5), biondinin D (12), and tiliroside (16), showed cytotoxicity against Jurkat T cells. In addition, (-)-parthenolide (2) exhibited cytotoxicity against the human cervical cancer HeLa cell line, the human breast cancer MCF-7, and human promyelocytic leukemia HL-60 cell lines.

Download Full-text