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- INF-γ, γ-interferon
- mTNF, transmembrane TNF-α
- PET, positron emission tomography
- SPECT, single photon emission computed tomography
- TNF, tumour-necrosis factor
It has long been known that apoptosis of T cells is an important mechanism for terminating inflammatory reactions.1 It was proposed over 10 years ago that defective apoptosis could play a role in the pathogenesis of inflammatory bowel disease.2 There is now substantial experimental and clinical evidence supporting this hypothesis.3
In Crohn’s disease there is an expansion in CD4 T-cell populations mediated by tumour necrosis factor (TNF) and γ-interferon (IFN-γ), which activate macrophages to release interleukin-6, interleukin-12 and TNF.4,5 These cytokines act to perpetuate the inflammatory reaction by reducing the susceptibility of T cells to die by apoptosis.3 In the uninflammed state, lamina propria T cells have a higher susceptibility to apoptosis than unstimulated T cells from the peripheral blood because of high expression of the apoptosis-inducing receptor Fas.6 In contrast to this, lamina propria T cells from patients with Crohn’s disease are resistant to apoptotic stimuli.7 These observations suggest that apoptosis limits the number of CD4 T cells in healthy individuals whereas in Crohn’s disease expansion of T-cell populations can occur without the restriction of apoptosis.
This resistance to induction of apoptosis is mediated by interleukin-12, the interleukin-6 receptor and TNF. Interleukin-12 is one of the most important cytokines in Crohn’s disease promoting Th1 T-cell differentiation. It also renders T cells resistant to Fas-induced apoptosis, possibly through inhibition of caspase 3 and 9, thereby prolonging T-cell survival.8 Early clinical studies have shown that antibodies that block the action of interleukin-12 reduce the severity of Crohn’s disease.9 Such antibodies also increase apoptosis in lamina propria T cells and reduce the severity of trinitrobenzene sulphonic acid experimental colitis.5
Interleukin-6 secreted by lamina propria macrophages and T cells also promotes the survival of T cells by inhibiting …
Competing Interest: None.
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