Methylxanthine-induced inhibition of the antigen- and superantigen-specific activation of T and B lymphocytes.

Methylxanthines have been shown to have a variety of effects on hematopoietic cell activation and function. These compounds inhibit cAMP-specific phosphodiesterase activity resulting in increased levels of intracellular cAMP. In the present study, we examined the effects of two methylxanthines, pentoxifylline (PTX) and caffeine, on the responses of both mouse and human lymphocytes to stimulation with polyclonal T- and B-cell mitogens, antigens, and the microbial superantigen, staphylococcal enterotoxin B (SEB). Both PTX and caffeine significantly inhibited mitogen- and SEB-induced proliferation by murine spleen cells, SEB- and antigen-induced proliferation and lymphokine secretion by murine Th1 and Th2 clones, and the generation of antigen-specific antibody producing murine spleen cells. These compounds also inhibited the proliferative responses of human lymphocytes to phytohemagglutinin, SEB, and tetanus toxoid. Efforts to determine whether these methylxanthine compounds mediated their inhibitory effects through a specific protein kinase pathway revealed a role for cAMP-dependent protein kinase A in methylxanthine-induced immunomodulation. However, it is possible that a protein kinase A-independent pathway may also be involved. These data demonstrate that the methylxanthines, PTX and caffeine, have profound effects on cells of the immune system and may have a potential use as immunotherapeutic agents in the treatment of various inflammatory conditions and autoimmune diseases.