cAMP inhibits induction of interleukin 2 but not of interleukin 4 in T cells.

Novak, Thomas J.; Rothenberg, Ellen V.

doi:10.1073/pnas.87.23.9353

Cited by 191 publications

(88 citation statements)

References 46 publications

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“…36,37 Inducible cAMP early repressor attenuates IL-2 expression by competitively binding to the transcription factor cAMP response element-binding protein. 38 Our study confirms the correlation between the cAMP signaling pathway and CY treatment, and our findings appear to contradict the clinical efficacy of the combination of chemotherapy and immunotherapy for the treatment of lymphoma patients.…”

Section: Western Blot Analysissupporting

confidence: 66%

Cyclic adenosine monophosphate involvement in low-dose cyclophosphamide-reversed immune evasion in a mouse lymphoma model

Dou

Liu

et al. 2012

Cell Mol Immunol

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Lymphoma cells mobilize many mechanisms to evade the immune system. There is substantial evidence that CD4 1 CD25 1 regulatory T cells (Tregs) play a key role in the control of immune evasion. Tregs can transfer cyclic adenosine monophosphate (cAMP) to effector T cells, suggesting an association between Tregs' immune-evasion role and the intracellular cAMP pathway. In this study, we used A20 B-cell lymphoma mice as aggressive tumor models to investigate the mechanism of the depletion of Tregs by low-dose cyclophosphamide (CY, 20 mg/kg). The tumor-bearing mice had longer survival times and slower tumor growth rates following treatment with CY, but its effects were temporary. Along with the depletion of Tregs by low-dose CY treatment, the expression of interleukin-2 (IL-2) in T effector cells increased, and intracellular cAMP concentrations in immune cells decreased. Our study demonstrates the ability of low-dose CY to reverse Tregs-mediated immune evasion in a mouse model. The changes in intracellular cAMP concentrations correlated with the upregulation of effector T cells and the downregulation of Tregs, indicating the close association of cAMP analogs and low-dose CY in the immune therapy of B-cell lymphoma.

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Section: Western Blot Analysissupporting

confidence: 66%

Cyclic adenosine monophosphate involvement in low-dose cyclophosphamide-reversed immune evasion in a mouse lymphoma model

Dou

Liu

et al. 2012

Cell Mol Immunol

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“…Cannabinoids have also been shown to inhibit N-type calcium channels in neuroblastoma-glioma cells (Mackie and Hille, 1992). As intracellular levels of both cyclic AMP and calcium that function as second messengers serve to modulate the immune response to external stimuli (Novak and Rothenberg, 1990;Whisler et al, 1992), one may speculate that cannabinoidinduced immunosuppression may be related to either adenylylc yclase inhibition and/or calcium channels through a peripheral cannabinoid receptor.…”

Section: Protein Expression Of the Cannabinoid Receptor In The U937 Cmentioning

confidence: 99%

Cannabinoid‐receptor expression in human leukocytes

Bouaboula

Rinaldi

Carayon

et al. 1993

European Journal of Biochemistry

321

205

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Marijuana and many of its constituent cannabinoids influence the central nervous system (CNS), probably through the cannabinoid receptor, which has recently been cloned in rat and human. While numerous reports have also described effects of cannabinoids on the immune system, the observation of both mRNA and cannabinoid receptor has hitherto been exclusively confined to the brain, a reported detection in the testis being the sole example of its presence at the periphery. Here we report the expression of the cannabinoid receptor on human immune tissues using a highly sensitive polymerase-chain-reaction-based method for mRNA quantification. We show that, although present in a much lower abundance than in brain, cannabinoid receptor transcripts are found in human spleen, tonsils and peripheral blood leukocytes. The distribution pattern displays important variations of the mRNA level for the cannabinoid receptor among the main human blood cell subpopulations. The rank order of mRNA levels in these cells is B cells > natural killer cells 2 polymorphonuclear neutrophils 2 T8 cells > monocytes > T4 cells. Cannabinoid-receptor mRNA, which is also found in monocytic, as well as T and B leukemia cell lines but not in Jurkat cells, presents a great diversity of expression on these cells as well, B-cell lines expressing a much higher level than T-cell lines. The cannabinoid receptor PCR products from leukocytes and brain are identical both in size and sequence suggesting a strong similarity between central and peripheral cannabinoid receptors. The expression of this receptor was demonstrated on membranes of the myelomonocytic U937 cells using the synthetic cannabinoid [3H]CP-55940 as ligand. The Kd determined from Scatchard analysis was 0.1 nM and the B,, for membranes was 525 fmol/mg protein. The demonstration of cannabinoid-receptor expression at both mRNA and protein levels on human leukocytes provides a molecular basis for cannabinoid action on these cells.

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“…The differential effects of GD1b, GT1b, and GQ1b on Th1 and Th2 production indicate the involvement of a certain signal(s) that differentially regulates Th1 and Th2 production. cAMP is one of these; PKA, cAMP-dependent protein kinase, may suppress Th1 cytokine production while it may not alter or enhance Th2 production (12)(13)(14). It is known that PHA transiently activates AC and elevates cAMP level and thus activates PKA (32).…”

Section: The Effects Of Gd1b Gt1b and Gq1b On Th1/th2 Promoter Actimentioning

confidence: 99%

Gangliosides GD1b, GT1b, and GQ1b Enhance IL-2 and IFN-γ Production and Suppress IL-4 and IL-5 Production in Phytohemagglutinin-Stimulated Human T Cells

Kanda

Watanabe

2001

The Journal of Immunology

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Gangliosides are sialic acid-containing glycolipids. We studied the in vitro effects of gangliosides on Th1 and Th2 cytokine production in PHA-stimulated human T cells. Gangliosides GD1b, GT1b, and GQ1b (each 100 nM) enhanced PHA-induced IL-2 secretion of peripheral blood T cells ∼4-fold and enhanced that of IFN-γ 3- to 4-fold compared with controls. These gangliosides decreased PHA-induced IL-4 secretion by 50–53% and that of IL-5 by 53–63% compared with controls, respectively. The other gangliosides did not alter the secretion of Th1 or Th2 cytokines. RT-PCR showed that GD1b, GT1b, and GQ1b enhanced PHA-induced IL-2 and IFN-γ transcription and suppressed that of IL-4 and IL-5. Transient transfection assays of Jurkat T cells showed that GD1b, GT1b, and GQ1b enhanced PHA-induced IL-2 and IFN-γ promoter activities but suppressed those of IL-4 and IL-5. The cAMP analogue dibutyryl cAMP and the cAMP-elevating agents forskolin and 3-isobutyl-1-methylxanthine each reversed GD1b-, GT1b-, and GQ1b-induced stimulation of IL-2 and IFN-γ production and inhibition of IL-4 and IL-5 production at the levels of proteins, transcription, and promoter activities. GD1b, GT1b, and GQ1b suppressed PHA-induced increase in cAMP level in T cells. These gangliosides suppressed PHA-stimulated adenylate cyclase activity in T cells. These results suggest that GD1b, GT1b, and GQ1b may enhance Th1 cytokine production while suppressing Th2 production by inhibiting adenylate cyclase activity.

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cAMP inhibits induction of interleukin 2 but not of interleukin 4 in T cells.

Cited by 191 publications

References 46 publications

Cyclic adenosine monophosphate involvement in low-dose cyclophosphamide-reversed immune evasion in a mouse lymphoma model

Cyclic adenosine monophosphate involvement in low-dose cyclophosphamide-reversed immune evasion in a mouse lymphoma model

Cannabinoid‐receptor expression in human leukocytes

Gangliosides GD1b, GT1b, and GQ1b Enhance IL-2 and IFN-γ Production and Suppress IL-4 and IL-5 Production in Phytohemagglutinin-Stimulated Human T Cells

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