Regulation of IL-15-stimulated TNF-α production by rolipram

Chitta S. Kasyapa, Carrie L. Stentz, Michael P. Davey, Daniel W. Carr

Research output: Contribution to journalArticlepeer-review

32 Scopus citations


Agents that increase intracellular cAMP have been shown to reduce joint inflammation in experimental arthritis, presumably by lowering the release of proinflammatory cytokines, such as TNF-α. Recent studies suggest that, in joints of patients with rheumatoid arthritis, TNF-α release from macrophages is triggered by their interaction with IL-15-stimulated T lymphocytes. In this report, we analyze the effect of rolipram, a cAMP-specific phosphodiesterase inhibitor, on TNF-α production in this experimental system. Cocultures of U937 cells with IL-15-stimulated T cells, but not control T cells, resulted in increased release of TNF-α. Pretreatment of T cells with rolipram or cAMP analogues inhibited the IL-15-stimulated increases in proliferation, expression of cell surface molecules CD69, ICAM- 1, and LFA-1, and release of TNF-α from macrophages. Addition of PMA to T cells dramatically increased the expression of cell surface molecules, but had little or no effect on TNF-α release from either T cells or from cocultures, suggesting that other surface molecules must also be involved in T cell/macrophage contact-mediated production of TNF-α. Addition of PMA synergistically increased the proliferation of IL-15-stimulated T cells and the secretion of TNF-α from IL-15-stimulated T cell/macrophage cocultures. Rolipram and 8-(4-chlorophenylthio)-cAMP (CPT-cAMP) blocked these increases. Measurement of protein kinase A (PKA) activity and the use of inhibitory cAMP analogues (RpCPT-cAMP) confirmed that rolipram worked by stimulating PKA. These data suggest that PKA-activating agents, such as rolipram, can block secretion of TNF-α from macrophages by inhibiting T cell activation and expression of surface molecules.

Original languageEnglish (US)
Pages (from-to)2836-2843
Number of pages8
JournalJournal of Immunology
Issue number5
StatePublished - Sep 1 1999

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology


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