SYM-49-04

Switching on the anti-inflammatory function of tristetraprolin (TTP) with PP2A activators: an off-switch for corticosteroid-insensitive inflammation in COPD

PM Nair1,2, MM Rahman3, NN Rumzhum3, MR Starkey1,2, TJ Haw1,2, G Liu1,2, JC Morris4, NM Verrills2, AR Clark5, PM Hansbro1 and AJ Ammit6,7

  1. Hunter Medical Research Institute
  2. University of Newcastle
  3. University of Sydney
  4. University of NSW
  5. University of Birmingham, UK
  6. Woolcock Institute of Medical Research
  7. University of Technology Sydney

Chronic obstructive pulmonary disease (COPD) is a progressive lung disease driven by inflammation. The lack of effective therapies for COPD means there is an urgent need to identify therapeutic strategies that targets the underlying mechanism. This is the promise of tristetraprolin (TTP). TTP is a critically important anti-inflammatory protein that post-transcriptionally suppresses many pro-inflammatory factors, including cytokines that drive the pathogenesis of COPD. TTP's anti-inflammatory function is controlled by phosphorylation (phosphorylated – OFF; unphosphorylated – ON). We have developed innovative tools to switch TTP on and turn off inflammation in in vivoand in vitro models of chronic respiratory disease. We subjected a knock-in mouse strain in which endogenous TTP cannot be inactivated to experimental models of respiratory disease characterized by corticosteroid resistance, including cigarette smoke-induced experimental COPD. We have discovered that active TTP represses hallmark features of human COPD in vivo and represses inflammation when corticosteroids cannot. Exploiting the potential demonstrated with the TTP knock-in mouse we can develop novel anti-inflammatory strategies for COPD. We can switch TTP on by activating protein phosphatase 2A (PP2A); the phosphatase responsible for dephosphorylating (and hence activating) TTP. This is achieved in vitro in cellular models of respiratory inflammation by activating PP2A with small molecules to switch TTP on and turn off production of chemoattractant cytokines. Thus, we are uniquely positioned to exploit the potential of TTP: an off-switch for corticosteroid-insensitive inflammation in COPD.