Z-IETD-FMK

Z-IETD-FMK is an inhibitor of caspase 8 [1].

Z-IETD-FMK inhibits T cell proliferation induced by PHA or anti-CD3 plus anti-CD28 without toxicity of resting T cells. The mechanism of this inhibition of Z-IETD-FMK has been proved not through the effect on IL-2 secretion or IFN-γ production but the decrease of CD25 expression. Experiments show that Z-IETD-FMK has no effect on normal cell growth when there is no activation signal. Z-IETD-FMK has also been found to significantly inhibit NF-κB activation when the concentration is 100μM [1].

Apart from the ability of inhibiting cell proliferation, Z-IETD-FMK is reported to inhibit TRAIL-mediated killing in cells. It protects the procaspases 9, 2, and 3, and protects PARP to a similar extent in both HCT116 and SW480 cells [2].

References:
[1] C.P. Lawrence, S.C. Chow. Suppression of human T cell proliferation by the caspase inhibitors, z-VAD-FMK and z-IETD-FMK is independent of their caspase inhibition properties. Toxicology and Applied Pharmacology. 2012, 265: 103-112.
[2] Nesrin Özören, Kunhong Kim, Timothy F. Burns, et al. The caspase 9 inhibitor Z-LEHD-FMK protects human liver cells while permitting death of cancer cells exposed to tumor necrosis factor-related apoptosis-inducing ligand. Cancer Research. 2000, 60: 6259-6265.

Suppression of human T cell proliferation by the caspase inhibitors, z-VAD-FMK and z-IETD-FMK is independent of their caspase inhibition properties.[Pubmed:22982538]

Toxicol Appl Pharmacol. 2012 Nov 15;265(1):103-12.

The caspase inhibitors, benzyloxycarbony (Cbz)-l-Val-Ala-Asp (OMe)-fluoromethylketone (z-VAD-FMK) and benzyloxycarbonyl (Cbz)-Ile-Glu (OMe)-Thr-Asp (OMe)-FMK (Z-IETD-FMK) at non-toxic doses were found to be immunosuppressive and inhibit human T cell proliferation induced by mitogens and IL-2 in vitro. Both caspase inhibitors were shown to block NF-kappaB in activated primary T cells, but have little inhibitory effect on the secretion of IL-2 and IFN-gamma during T cell activation. However, the expression of IL-2 receptor alpha-chain (CD25) in activated T cells was inhibited by both z-VAD-FMK and Z-IETD-FMK, whereas the expression of the early activated T cell marker, CD69 was unaffected. During primary T cell activation via the antigen receptor, both caspase-8 and caspase-3 were activated and processed to their respective subunits, but neither caspase inhibitors had any effect on the processing of these two caspases. In sharp contrast both caspase inhibitors readily blocked apoptosis and the activation of caspases during FasL-induced apoptosis in activated primary T cells and Jurkat T cells. Collectively, the results demonstrate that both z-VAD-FMK and Z-IETD-FMK are immunosuppressive in vitro and inhibit T cell proliferation without blocking the processing of caspase-8 and caspase-3.

Z-IETD-FMK (Z-IE(OMe)TD(OMe)-FMK) is a selective and cell permeable caspase-8 inhibitor. Z-IETD-FMK is also a granzyme B inhibitor.

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