TGF-β activity restoration and phosphodiesterase 4 inhibition as therapeutic options for inflammatory bowel diseases.

In the last decades, the better understanding of inflammatory bowel diseases (IBD) pathogenesis has contributed to the identification of new therapeutic targets that can be modulated to induce and maintain disease remission. Monoclonal antibodies against tumor necrosis factor, interleukin (IL)-12/IL-23p40, and the integrin α4β7 and inhibitors of Janus kinase molecules are valid compounds to limit the function of molecules implicated in the control of IBD-related inflammation. However, not all patients respond to treatment with such drugs, some of them lose response over time and others develop serious side effects, such as infections or malignancies, which lead to the discontinuation of the therapy. Thus, an intensive research is ongoing with the goal to identify new targets and develop novel therapeutic options. In this context, restoration of TGF-β activity and inhibition of phosphodiesterase 4 (PD4) represent two relevant strategies. TGF-β is an immunesuppressive cytokine, whose activity is severely impaired in IBD due to the abundance of the intracellular inhibitor Smad7. Knockdown of Smad7 with a specific antisense oligonucleotide restores TGF-β signalling and dampens effector immune responses in pre-clinical studies and initial clinical trials in Crohn's disease patients, even though a recent phase 3 trial was discontinued due to an apparent inefficacy. PD4 inhibition determines the increase of intracellular levels of cyclic adenosine monophosphate, a mechanism that decreases pro-inflammatory cytokine production. A recent phase 2 study has shown that oral administration of PD4 associates with clinical benefit in patients with ulcerative colitis. In this article, we review the rationale and the available data relative to the use of these two agents in IBD.