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Research ArticleINFLAMMATION AND IMMUNOPHARMACOLOGY

Evidence for Cannabinoid Receptor-Dependent and -Independent Mechanisms of Action in Leukocytes

Barbara L. Faubert Kaplan, Cheryl E. Rockwell and Norbert E. Kaminski
Journal of Pharmacology and Experimental Therapeutics September 2003, 306 (3) 1077-1085; DOI: https://doi.org/10.1124/jpet.103.051961
Barbara L. Faubert Kaplan
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Cheryl E. Rockwell
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Norbert E. Kaminski
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Abstract

Cannabinoids exhibit immunosuppressive actions that include inhibition of interleukin-2 production in response to a variety of T cell activation stimuli. Traditionally, the effects of these compounds have been attributed to cannabinoid receptors CB1 and CB2, both of which are expressed in mouse splenocytes. Therefore, N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorphenyl)-4-methyl-H-pyrazole-3 carboxyamidehydrochloride (SR141716A), a CB1 antagonist, and N-[(1S)-endo-1,3,3,-trimethyl-bicyclo[2,2,1]heptan-2-yl]-5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)-pyrazole-3-carboxamide (SR144528), a CB2 antagonist, were used to investigate the role of cannabinoid receptors in the cannabinoid-induced inhibition of phorbol ester plus calcium ionophore (PMA/Io)-stimulated interleukin-2 production by mouse splenocytes. PMA/Io-stimulated interleukin-2 production was inhibited by cannabinol, cannabidiol, and both WIN 55212-2 stereoisomers with a rank order potency of R-(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]pyrrolo[1,2,3-de]-1,4-benzoxazinyl]-(1-napthanlenyl) methanone mesylate (WIN 55212-2) ≈ cannabidiol > S-(-)-[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]pyrrolo[1,2,3-de]-1,4-benzoxazinyl]-(1-napthanlenyl) methanone mesylate (WIN 55212-3) ≈ cannabinol. Cannabinoid-induced inhibition of PMA/Io-stimulated interleukin-2 was not attenuated by the presence of both SR144528 and SR141716A. Using pertussis toxin to address the role of G protein-coupled receptors in this response, it was determined that pertussis toxin treatment did not attenuate cannabinol-induced inhibition of PMA/Io-stimulated interleukin-2. With the demonstration that cannabinoid-induced inhibition of PMA/Io-stimulated interleukin-2 was not mediated via CB1 or CB2, alternative targets of cannabinoids in T cells were examined. Specifically, it was demonstrated that cannabinoids elevated intracellular calcium concentration in resting splenocytes and that the cannabinol-induced elevation in intracellular calcium concentration was attenuated by treatment with both SR144528 and SR141716A. Interestingly, pretreatment of splenocytes with agents that elevate intracellular calcium concentration inhibited PMA/Io-stimulated interleukin-2 production, suggesting that an elevation in intracellular calcium concentration might be involved in the mechanism of interleukin-2 inhibition. These studies suggest that immune modulation produced by cannabinoids involves multiple mechanisms, which might be both cannabinoid receptor-dependent and -independent.

Footnotes

  • This work was supported by funds from National Institute on Drug Abuse Grant DA07908.

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

  • DOI: 10.1124/jpet.103.051961.

  • ABBREVIATIONS: PMA/Io, phorbol ester plus calcium ionophore; CB, cannabinoid; SR141716A, N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorphenyl)-4-methyl-H-pyrazole-3 carboxyamidehydrochloride; SR144528, N-[(1S)-endo-1,3,3,-trimethyl bicyclo [2,2,1] heptan-2-yl]-5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)-pyrazole-3-carboxamide; WIN-2 (WIN 55212-2), R-(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]pyrrolo[1,2,3-de]-1,4-benzoxazinyl]-(1-napthanlenyl) methanone mesylate; WIN-3 (WIN 55212-3), S-(-)-[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]pyrrolo[1,2,3-de]-1,4-benzoxazinyl]-(1-napthanlenyl) methanone mesylate; ELISA, enzyme-linked immunosorbent assay; PMA, phorbol 12-myristate 13-acetate; RT, room temperature; AM, acetoxymethyl ester; [Ca2+]i, intracellular calcium concentration; [Ca2+]e, extracellular calcium concentration; Δ9-THC, Δ9-tetrahydrocannabinol; A23187, calcimycin.

    • Received March 24, 2003.
    • Accepted May 27, 2003.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 306 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 306, Issue 3
1 Sep 2003
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Research ArticleINFLAMMATION AND IMMUNOPHARMACOLOGY

Evidence for Cannabinoid Receptor-Dependent and -Independent Mechanisms of Action in Leukocytes

Barbara L. Faubert Kaplan, Cheryl E. Rockwell and Norbert E. Kaminski
Journal of Pharmacology and Experimental Therapeutics September 1, 2003, 306 (3) 1077-1085; DOI: https://doi.org/10.1124/jpet.103.051961

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Research ArticleINFLAMMATION AND IMMUNOPHARMACOLOGY

Evidence for Cannabinoid Receptor-Dependent and -Independent Mechanisms of Action in Leukocytes

Barbara L. Faubert Kaplan, Cheryl E. Rockwell and Norbert E. Kaminski
Journal of Pharmacology and Experimental Therapeutics September 1, 2003, 306 (3) 1077-1085; DOI: https://doi.org/10.1124/jpet.103.051961
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