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Modulation by cannabinol of interleukin (IL)-2 and IL-4 expression is closely correlated with the regulation of nuclear factor of activated T cells (NF-AT).

Record Type:	Electronic resources : Monograph/item
Title/Author:	Modulation by cannabinol of interleukin (IL)-2 and IL-4 expression is closely correlated with the regulation of nuclear factor of activated T cells (NF-AT)./
Author:	Jan, Tong-Rong.
Published:	Ann Arbor : ProQuest Dissertations & Theses, : 2001,
Description:	201 p.
Notes:	Source: Dissertations Abstracts International, Volume: 63-04, Section: B.
Contained By:	Dissertations Abstracts International63-04B.
Subject:	Pharmacology. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3009122
ISBN:	9780493184432

Modulation by cannabinol of interleukin (IL)-2 and IL-4 expression is closely correlated with the regulation of nuclear factor of activated T cells (NF-AT).
Jan, Tong-Rong.

Modulation by cannabinol of interleukin (IL)-2 and IL-4 expression is closely correlated with the regulation of nuclear factor of activated T cells (NF-AT). - Ann Arbor : ProQuest Dissertations & Theses, 2001 - 201 p.

Source: Dissertations Abstracts International, Volume: 63-04, Section: B.

Thesis (Ph.D.)--Michigan State University, 2001.

This item must not be sold to any third party vendors.

Plant-derived cannabinoids have been well established as immune modulators. Previous studies have demonstrated that T cell accessory function is involved in the inhibition of humoral immune responses by cannabinoids. To further investigate the underlying mechanism for cannabinoid-mediated immune modulation, the effect of CBN on the expression of IL-2 and IL-4, two critical cytokines involved in antibody response against T cell-dependent antigens was characterized. CBN elicited contrasting effects on IL-2 protein secretion by T cells, which was dependent on the magnitude of the T cell activation stimulus. IL-2 secretion induced by optimal activation stimuli was suppressed, whereas IL-2 secretion induced by sub-optimal stimuli was enhanced. The CBN mediated enhancement of IL-2 secretion was closely associated with an enhancement in IL-2 steady state mRNA expression, and with an increase in ERK MAP kinase activation. More in depth studies identified the distal NF-AT site in the IL-2 promoter as one downstream response element involved in the increased transcription of IL-2 by CBN. In contrast, CBN and Δ9-THC treatment inhibited IL-4 secretion by T cells under all T cell activation conditions tested. The IL-4 steady state mRNA expression by PMA/Io-activated EL4 T cells was also inhibited by cannabinoids. Concordantly, DNA binding activity to the IL-4 P0 NF-AT site was diminished in the presence of cannabinoids. Additionally, RNase protection assays demonstrated that Δ9-THC suppressed the expression of three separate cytokine genes that are regulated by NF-AT, IL-2, IL-4 and IL-5, under the conditions of optimal T cell activation. The in vitro studies were extended to an in vivo model of allergic airway disease critically dependent on T cell cytokines, including IL-2 and IIL-4. In this model, both IL-2 and IL-4 mRNA expression in the lungs of A/J mice sensitized and challenged with ovalbumin was attenuated by administration of CBN or Δ9-THC The level of ovalbumin-specific serum IgE, an important mediator of the allergic airway response, was concordantly attenuated by both cannabinoids. Collectively, these results confirm that CBN and Δ9-THC-inhibition of IL-2 and IL-4 can be produced both in vivo and in vitro. The putative role of cannabinoid receptors and the cAMP signaling pathway to which CB1 and CB2 negatively couple, in CBN-mediated modulation of IL-2 and IL-4 expression was investigated. The CBN-mediated effects were not attenuated by (1) dibutyryl-cAMP treatment, (2) pre-incubation of T cells with pertussis toxin, and (3) pretreatment of T cells with cannabinoid receptor antagonists. Furthermore, comparative studies employing the cannabinoid congeners cannabidiol, CP55,940 and WIN55212 demonstrated a lack of correlation between their activity of cytokine modulation and affinity of CB1 and CB2 binding. In spite of this, the WIN55212 enantiomers, produced stereo-selective inhibition of IL-4. Collectively, the present studies demonstrate that cannabinoid-mediated modulation of IL-2 and IL-4 expression by T cells is closely associated with the regulation of NF-AT and ERK activation. In addition, these studies suggest that cannabinoid modulation of IL-2 and IL-4 is apparently not mediated through the negative modulation of the cAMP pathway via cannabinoid receptors.

ISBN: 9780493184432Subjects--Topical Terms:

634543
Pharmacology.
Subjects--Index Terms:

Allergic airway disease

Modulation by cannabinol of interleukin (IL)-2 and IL-4 expression is closely correlated with the regulation of nuclear factor of activated T cells (NF-AT).
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245 1 0 $a Modulation by cannabinol of interleukin (IL)-2 and IL-4 expression is closely correlated with the regulation of nuclear factor of activated T cells (NF-AT).
260 1 $a Ann Arbor : $b ProQuest Dissertations & Theses, $c 2001
300 $a 201 p.
500 $a Source: Dissertations Abstracts International, Volume: 63-04, Section: B.
500 $a Publisher info.: Dissertation/Thesis.
500 $a Advisor: Kaminski, Norbert E.
502 $a Thesis (Ph.D.)--Michigan State University, 2001.
506 $a This item must not be sold to any third party vendors.
506 $a This item must not be added to any third party search indexes.
520 $a Plant-derived cannabinoids have been well established as immune modulators. Previous studies have demonstrated that T cell accessory function is involved in the inhibition of humoral immune responses by cannabinoids. To further investigate the underlying mechanism for cannabinoid-mediated immune modulation, the effect of CBN on the expression of IL-2 and IL-4, two critical cytokines involved in antibody response against T cell-dependent antigens was characterized. CBN elicited contrasting effects on IL-2 protein secretion by T cells, which was dependent on the magnitude of the T cell activation stimulus. IL-2 secretion induced by optimal activation stimuli was suppressed, whereas IL-2 secretion induced by sub-optimal stimuli was enhanced. The CBN mediated enhancement of IL-2 secretion was closely associated with an enhancement in IL-2 steady state mRNA expression, and with an increase in ERK MAP kinase activation. More in depth studies identified the distal NF-AT site in the IL-2 promoter as one downstream response element involved in the increased transcription of IL-2 by CBN. In contrast, CBN and Δ9-THC treatment inhibited IL-4 secretion by T cells under all T cell activation conditions tested. The IL-4 steady state mRNA expression by PMA/Io-activated EL4 T cells was also inhibited by cannabinoids. Concordantly, DNA binding activity to the IL-4 P0 NF-AT site was diminished in the presence of cannabinoids. Additionally, RNase protection assays demonstrated that Δ9-THC suppressed the expression of three separate cytokine genes that are regulated by NF-AT, IL-2, IL-4 and IL-5, under the conditions of optimal T cell activation. The in vitro studies were extended to an in vivo model of allergic airway disease critically dependent on T cell cytokines, including IL-2 and IIL-4. In this model, both IL-2 and IL-4 mRNA expression in the lungs of A/J mice sensitized and challenged with ovalbumin was attenuated by administration of CBN or Δ9-THC The level of ovalbumin-specific serum IgE, an important mediator of the allergic airway response, was concordantly attenuated by both cannabinoids. Collectively, these results confirm that CBN and Δ9-THC-inhibition of IL-2 and IL-4 can be produced both in vivo and in vitro. The putative role of cannabinoid receptors and the cAMP signaling pathway to which CB1 and CB2 negatively couple, in CBN-mediated modulation of IL-2 and IL-4 expression was investigated. The CBN-mediated effects were not attenuated by (1) dibutyryl-cAMP treatment, (2) pre-incubation of T cells with pertussis toxin, and (3) pretreatment of T cells with cannabinoid receptor antagonists. Furthermore, comparative studies employing the cannabinoid congeners cannabidiol, CP55,940 and WIN55212 demonstrated a lack of correlation between their activity of cytokine modulation and affinity of CB1 and CB2 binding. In spite of this, the WIN55212 enantiomers, produced stereo-selective inhibition of IL-4. Collectively, the present studies demonstrate that cannabinoid-mediated modulation of IL-2 and IL-4 expression by T cells is closely associated with the regulation of NF-AT and ERK activation. In addition, these studies suggest that cannabinoid modulation of IL-2 and IL-4 is apparently not mediated through the negative modulation of the cAMP pathway via cannabinoid receptors.
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650 4 $a Anatomy & physiology. $3 3434423
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650 4 $a Molecular biology. $3 517296
653 $a Allergic airway disease
653 $a Cannabinol
653 $a Immune modulators
653 $a Interleukin
653 $a Nuclear factor of activated T cells
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710 2 $a Michigan State University. $3 676168
773 0 $t Dissertations Abstracts International $g 63-04B.
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