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Modulation of cytokine production by cyclic adenosine monophosphate analogs in human leukocytes

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Abstract
Cyclic adenosine monophosphate (cAMP) is a well-known second messenger that operates through different signaling molecules, including protein kinase A (PKA) and guanine exchange proteins directly activated by cAMP (EPAC). Cell-permeable cAMP analogs such as 8-(4-chloro-phenyl-thio)-cAMP (8-pCPT-cAMP) modulate cytokine secretion by different leukocyte subsets, including T cells and monocytes. Since cAMP-modulating drugs such as phosphodiesterase inhibitors are being tested in inflammatory disorders such as asthma and chronic obstructive lung disease, it is important to obtain more insight into the regulation of cytokine production by cAMP. To address the signaling molecules involved in cAMP-mediated modulation of cytokine production, we used cAMP derivatives such as N(6)-benzoyladenosine-cAMP (6-Bnz-cAMP) and 8-pCPT-2-O-methyl cAMP (8-pCPT-2'-O-Me-cAMP), which selectively activate either PKA or EPAC, respectively. We show that in T cells, 6-Bnz-cAMP exerts similar globally inhibiting effects on cytokine secretion as 8-pCPT-cAMP, indicating that these effects are mediated by PKA. On the contrary, 8-pCPT-2'-O-Me-cAMP specifically inhibits the production of interleukin-10 (IL-10) in lipopolysaccharide-activated T-cell-depleted peripheral blood mononuclear cells, whereas the production of IL-1 beta, tumor necrosis factor alpha, and IL-12 is not or hardly affected. Inhibition by 8-pCPT-2'-O-Me-cAMP of IL-10 production was confirmed using purified monocytes. Further, in B cells 6-Bnz-cAMP, but not 8-pCPT-2'-O-Me-cAMP, stimulated IL-10 production. In conclusion, cAMP stimulates IL-10 production via PKA in activated B cells, but inhibits IL-10 production in activated monocytes through EPAC. We speculate that selective effects of PKA and EPAC on cytokine production in leukocyte subsets open up therapeutic possibilities using selective activators or inhibitors of EPAC or PKA.
Keywords
AMP, CAMP, CELLS, PDE4 INHIBITORS, RHEUMATOID-ARTHRITIS, IL-10 PRODUCTION, PROTEIN-KINASE-A, HUMAN T-LYMPHOCYTES, MULTIPLE, EPAC

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Chicago
Gerlo, Sarah, Peggy Verdood, and Ron Kooijman. 2010. “Modulation of Cytokine Production by Cyclic Adenosine Monophosphate Analogs in Human Leukocytes.” Journal of Interferon and Cytokine Research 30 (12): 883–891.
APA
Gerlo, S., Verdood, P., & Kooijman, R. (2010). Modulation of cytokine production by cyclic adenosine monophosphate analogs in human leukocytes. JOURNAL OF INTERFERON AND CYTOKINE RESEARCH, 30(12), 883–891.
Vancouver
1.
Gerlo S, Verdood P, Kooijman R. Modulation of cytokine production by cyclic adenosine monophosphate analogs in human leukocytes. JOURNAL OF INTERFERON AND CYTOKINE RESEARCH. 2010;30(12):883–91.
MLA
Gerlo, Sarah, Peggy Verdood, and Ron Kooijman. “Modulation of Cytokine Production by Cyclic Adenosine Monophosphate Analogs in Human Leukocytes.” JOURNAL OF INTERFERON AND CYTOKINE RESEARCH 30.12 (2010): 883–891. Print.
@article{6969199,
  abstract     = {Cyclic adenosine monophosphate (cAMP) is a well-known second messenger that operates through different signaling molecules, including protein kinase A (PKA) and guanine exchange proteins directly activated by cAMP (EPAC). Cell-permeable cAMP analogs such as 8-(4-chloro-phenyl-thio)-cAMP (8-pCPT-cAMP) modulate cytokine secretion by different leukocyte subsets, including T cells and monocytes. Since cAMP-modulating drugs such as phosphodiesterase inhibitors are being tested in inflammatory disorders such as asthma and chronic obstructive lung disease, it is important to obtain more insight into the regulation of cytokine production by cAMP. To address the signaling molecules involved in cAMP-mediated modulation of cytokine production, we used cAMP derivatives such as N(6)-benzoyladenosine-cAMP (6-Bnz-cAMP) and 8-pCPT-2-O-methyl cAMP (8-pCPT-2'-O-Me-cAMP), which selectively activate either PKA or EPAC, respectively. We show that in T cells, 6-Bnz-cAMP exerts similar globally inhibiting effects on cytokine secretion as 8-pCPT-cAMP, indicating that these effects are mediated by PKA. On the contrary, 8-pCPT-2'-O-Me-cAMP specifically inhibits the production of interleukin-10 (IL-10) in lipopolysaccharide-activated T-cell-depleted peripheral blood mononuclear cells, whereas the production of IL-1 beta, tumor necrosis factor alpha, and IL-12 is not or hardly affected. Inhibition by 8-pCPT-2'-O-Me-cAMP of IL-10 production was confirmed using purified monocytes. Further, in B cells 6-Bnz-cAMP, but not 8-pCPT-2'-O-Me-cAMP, stimulated IL-10 production. In conclusion, cAMP stimulates IL-10 production via PKA in activated B cells, but inhibits IL-10 production in activated monocytes through EPAC. We speculate that selective effects of PKA and EPAC on cytokine production in leukocyte subsets open up therapeutic possibilities using selective activators or inhibitors of EPAC or PKA.},
  author       = {Gerlo, Sarah and Verdood, Peggy and Kooijman, Ron},
  issn         = {1079-9907},
  journal      = {JOURNAL OF INTERFERON AND CYTOKINE RESEARCH},
  keywords     = {AMP,CAMP,CELLS,PDE4 INHIBITORS,RHEUMATOID-ARTHRITIS,IL-10 PRODUCTION,PROTEIN-KINASE-A,HUMAN T-LYMPHOCYTES,MULTIPLE,EPAC},
  language     = {eng},
  number       = {12},
  pages        = {883--891},
  title        = {Modulation of cytokine production by cyclic adenosine monophosphate analogs in human leukocytes},
  url          = {http://dx.doi.org/10.1089/jir.2009.0021},
  volume       = {30},
  year         = {2010},
}

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