Apoptosis inhibition in T cells triggers the expression of proinflammatory cytokines--implications for the CNS.
Stimulation of death receptors such as CD95 or TNF-R1 results in rapid onset of apoptosis. Here we show that inhibition of death receptor-induced apoptosis by the broad range caspase inhibitor ZVAD causes a switch from apoptotic to proinflammatory signaling. In previous studies we have reported that caspase inhibitors induce expression of various proinflammatory cytokines in CD95-stimulated primary T cells, such as TNF-alpha, IFN-gamma and GM-CSF. In this study we provide further evidence for the proinflammatory activity of CD95. Stimulation of CD95 by agonistic antibodies (7C11) resulted in expression of IL-2 in primary T cells, which was further enhanced when caspase activity was blocked by ZVAD. Moreover, CD95 triggered expression of IL-4 and IL-8 when caspase activity was inhibited, but not in the absence of ZVAD. Our findings are of significant importance for the CNS as changes in the cytokine pattern in the periphery affects the entry of various immune cells into the brain. Moreover, invading activated T cells can also directly influence the cytokine profile within the brain, triggering signaling cascades that eventually lead to neuronal cell death. The use of caspase inhibitors to prevent apoptotic cell death should be carefully evaluated in the management of systemic and CNS diseases.
Scheller
C
C
Institute of Virology and Immunobiology, Würzburg, Germany. scheller@vim.uni-wuerzburg.de
Riederer
P
P
Gerlach
M
M
Koutsilieri
E
E
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000906:Antibodies / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism*; D004347:Drug Interactions; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D008954:Models, Biological; D018696:Neuroprotective Agents / Q000494:pharmacology; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism*; D019014:fas Receptor / Q000276:immunology
D000590:Amino Acid Chloromethyl Ketones; D000906:Antibodies; D016207:Cytokines; D018696:Neuroprotective Agents; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D019014:fas Receptor