Inhibition of cytotoxicity and cytokine release of CD8+ HIV-specific cytotoxic T lymphocytes by pentoxifylline

Abstract

HIV-specific cytotoxic T lymphocytes (CTLs) are an important component of the host immune response against HIV infection, and these cells release a variety of cytokines when they meet their target antigen. Since the phosphodiesterase inhibitor pentoxifylline is being used as a therapeutic agent in clinical trials of HIV infection due to its inhibitory effect on virus replication in vitro, we examined the effect of pentoxifylline on cytotoxicity and cytokine secretion by HIV-specific CD8+ CTLs. Pentoxifylline inhibited cytotoxicity of CTLs and suppressed interferon-gamma, tumor necrosis factor-alpha, and granulocyte-macrophage colony-stimulating factor release by these cells at the transcription level. Suppression of cytokine release resulted in reduced capacity of the CTLs to induce HLA class I and ICAM-1 expression and to stimulate HIV-1 replication. These results suggest that inhibition of HIV-specific CD8+ CTLs by pentoxifylline may be therapeutically relevant. Moreover, this study extends previous observations by demonstrating that, in addition to its ability to suppress cytokine production by macrophages and CD4+ T helper cells, pentoxifylline may inhibit cytotoxicity and cytokine secretion by antigen-specific CD8+ cytotoxic T lymphocytes.