Impact of cAMP on the T‐cell response to type II collagen

Abstract

SUMMARYThere is considerable interest in the possible use of cAMP-elevating agents in the treatment of autoimmune diseases such as rheumatoid arthritis. The objective of this study was to evaluate the impact of different cAMP-elevating agents on the T-cell response to type II collagen within the context of collagen-induced arthritis, a murine model of rheumatoid arthritis. Spleen cells or lymph node cells from type-II-collagen-immunized DBA/1 mice were cultured in the presence of type II collagen plus one of ®ve different cAMP-elevating agents: rolipram, forskolin, prostaglandin E 2 , 8-bromo-cAMP, or cholera toxin. Levels of interferon-g (IFN-g), interleukin-4 (IL-4) and IL-5 were measured in culture supernatants by enzyme-linked immunosorbent assay. All of the cAMP-elevating agents tested were found to profoundly suppress IFN-g production in a dose-dependent manner. IL-4 and IL-5 production was slightly upregulated at low concentrations of the cAMP-elevating agents and was modestly suppressed at the highest concentrations of cAMP-elevating agents. Experiments were then carried out to determine whether T cells were directly affected by cAMP-elevating agents or whether the immunomodulatory effects were mediated via antigen-presenting cells. Pulsing T cells alone for a brief period with cholera toxin produced an almost identical effect to pulsing antigenpresenting cells alone, i.e. down-regulation of proliferation, down-regulation of IFN-g production with little effect on IL-5 production. It was concluded that cAMP-elevating agents suppressed T helper type 1 responses to type II collagen to a greater extent than T helper type 2 responses. The cAMP-elevating agents could directly in¯uence the activity of T cells but, in addition, in¯uenced the ability of antigen-presenting cells to support T helper type 1 responses.

Direct Inhibition of T-Lymphocyte Activation by Anthrax Toxins In Vivo

“…Thus, levels of cAMP may have changed from inhibitory to immunoenhancing. Moderate increases in cAMP have previously been demonstrated to increase the production of IL-4 and IL-5 in T cells (31). Further, cAMP-inducing agents increased the production of IL-6 and IL-10 in UVB-irradiated human keratinocytes (16).…”

Beta-agonists modulate T-cell functions via direct actions on type 1 and type 2 cells

“…Consistent with our findings, Ozegbe et al recently reported a trend that low-dose PGE 2 enhances antigen-stimulated IL-5 production by mouse lymph node T cells. 64 In vivo, T cells are likely exposed to a wide range of levels of PGE 2 in a paracrine manner, depending on the intensity of local inflammation and the complement of infiltrating inflammatory cells.…”

Models of Rheumatoid Arthritis

“…IL-4 and IL-5 production was slightly upregulated at low concentrations of the cAMPelevating agents, and was modestly suppressed at the highest concentrations of cAMP-elevating agents (Ozegbe et al 2003). Experiments were then carried out to determine whether T cells were directly affected by cAMP-elevating agents or whether the immunomodulatory effects were mediated via APCs.…”

“…Pulsing T cells alone for a brief period with cholera toxin produced an almost identical effect to pulsing APCs alone, i.e. downregulation of proliferation, and downregulation of IFN-c production with little effect on IL-5 production (Ozegbe et al 2003).…”