There is growing evidence that the efficacy of anti-tumour necrosis factor α (TNF-α) therapies in Crohn’s disease (CD) may critically depend on the binding of the transmembrane precursor of TNF-α (mTNF-α), thus eliciting complex intracellular signalling events, a process described as “reverse signalling”.^1–3 In their recent paper (Gut 2004;53:70–7), Di Sabatino et al showed that infliximab reverted defective peripheral and lamina propria lymphocyte apoptosis in CD patients via a caspase dependent mechanism, further corroborating the findings of previous studies.^1–4 It has also been suggested that failure of another TNF binding agent, etanercept (Enbrel; a recombinant TNFR2:Fc fusion protein), to induce peripheral and lamina propria lymphocyte apoptosis,⁴ provides a possible molecular explanation for the lack of efficacy of etanercept in a randomised placebo controlled trial in active CD.⁵

However, the authors do not discuss other signalling pathways that are activated via ligation of transmembrane TNF-α by infliximab (for example, we have shown that infliximab also transiently activates p38 mitogen activated protein kinase (MAPK) in monocytes in vitro and in the lamina propria of CD patients in vivo³). Responders and non-responders to infliximab differ in the pattern of mucosal p38MAPK target phosphorylation, but not caspase-3 activation, further emphasising the complex modulation of intracellular signalling pathways beyond mere neutralisation of sTNF-α.⁶ To show if these signalling pathways are also activated in primary T cells, we analysed the influence of infliximab and etanercept on p38MAPK activation and apoptosis in an established model of non-transformed in situ activated T lymphocytes.^7,8

According to the findings of van den Brande et al,⁴ we observed PARP cleavage as a molecular hallmark of apoptosis in cultures grown with infliximab (fig 1A) but not in the presence of etanercept. Whereas no increase in phosphorylated p38MAPK …