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Elevation of cyclic adenosine monophosphate levels independently down regulates IL-1, IL-2, and IL-2 receptor (CD25)
1Laboratory of Immunology, INSERM U.80, CNRS UA 1177, Hôpital E. Herriot, Lyon, France.
Abstract:
In view of the central involvement of interleukin-1 (IL-1) in T-cell functions and the negative effects exerted by cyclic adenosine monophosphate (cAMP) on T-cell responses, we wondered whether these inhibitions rely on defects in IL-1 generation. We investigated the effect of a known cAMP elevating agent, cholera toxin (CT), on the generation of IL-1 from peripheral blood adherent cells as well as the role of IL-1 whenever IL-2 synthesis and IL-2 receptor (CD25 antigen) expression are inhibited. While augmenting intracellular cAMP concentration, CT inhibits from 20 to 40% the generation of IL-1 activity from E. coli lipopolysaccharide (LPS)-stimulated adherent cells. Theophylline (TH), a cAMP degradation blocking agent, induces the same decrease in IL-1 activity. The B chain of CT, devoid of cAMP activating potency, is not inhibitory. In systems where CT and TH dramatically inhibit the generation of IL-2 activity (80%), addition of exogenous IL-1 does not restore the ability of T-cells to produce or release IL-2. Moreover, CT- and dibutyryl (db)cAMP-induced inhibition of CD25 antigen expression is not overcome by exogenous IL-1, IL-2, nor by both interleukins. It is concluded that inhibition of IL-1 and IL-2 production are independent and that inhibition of CD25 antigen expression is independent of IL-1 and IL-2 modulation. Cholera toxin and cAMP influences on interleukin synthesis are discussed.
Insights
Cholera toxin (CT) and cyclic adenosine monophosphate (cAMP) inhibit interleukin-1 (IL-1) generation. However, IL-1 does not restore IL-2 production or CD25 expression when inhibited by cAMP, indicating independent pathways.
Area of Science:
- Immunology
- Cellular Biology
Background:
- Interleukin-1 (IL-1) is central to T-cell functions.
- Cyclic adenosine monophosphate (cAMP) negatively impacts T-cell responses.
- The relationship between cAMP, IL-1 generation, and T-cell inhibition requires clarification.
Purpose of the Study:
- To investigate the effect of cholera toxin (CT), a cAMP-elevating agent, on IL-1 generation.
- To determine the role of IL-1 in T-cell responses when IL-2 synthesis and CD25 expression are inhibited by cAMP.
- To elucidate the independence of IL-1 and IL-2 pathways in cAMP-mediated T-cell modulation.
Main Methods:
- Stimulation of peripheral blood adherent cells with E. coli lipopolysaccharide (LPS).
- Treatment with cholera toxin (CT), theophylline (TH), or CT B chain to modulate cAMP levels.
- Assessment of IL-1 activity generation.
- Evaluation of IL-2 activity and CD25 antigen expression.
- Addition of exogenous IL-1, IL-2, or both to assess restoration of function.
Main Results:
- CT and TH inhibited IL-1 generation by 20-40% in LPS-stimulated cells.
- The inhibitory effect of CT on IL-1 generation was dependent on its cAMP-activating potency.
- Exogenous IL-1 did not restore IL-2 production or CD25 expression inhibited by CT or dibutyryl cAMP (db)cAMP.
- CT and db)cAMP-induced inhibition of CD25 antigen expression was not overcome by IL-1, IL-2, or both.
Conclusions:
- Inhibition of IL-1 and IL-2 production by cAMP-elevating agents are independent processes.
- The inhibition of CD25 antigen expression by cAMP is independent of IL-1 and IL-2 modulation.
- Cholera toxin and cAMP influence interleukin synthesis through distinct mechanisms affecting T-cell responses.