Recurrent respiratory papillomas (RRP) are tumors of the respiratory airway, caused by HPVs 6/11. The disease is managed by surgery, but papillomas frequently recur due to activation of latent infection. Patients have an impaired immune response to HPV infection. Patients with RRP constitutively express COX-2 and its product PGE2 in the airway epithelium. Here we review the role of PGE2 in the pathobiology of RRP.
The role of PGE2was examined in primary cultured cells, a rabbit model system and in vivo in RRP patients. Papilloma cells, cultured in serum-free medium, were treated with PGE2 or celecoxib, a selective COX-2 inhibitor, and analyzed for proliferation, apoptosis, and HPV mRNA expression and for activation of specific signaling pathways. Immature Langerhans cells (LCs) were generated from blood monocytes of RRP patients and controls, and exposed to varying concentrations of the cytokine IL-36γ with/without added PGE2. Expression of proinflammatory cytokine/chemokine expression was quantified by qPCR. Rabbits were infected with cottontail rabbit papilloma virus (CRPV) to establish a latent infection, treated with oral celecoxib or carrier, and treated with UV light to activate latency, which was measured by PCR. In a clinical trial, RRP patients were treated with celecoxib or placebo, the persistence of HPV latency was determined by PCR, and clinical responses were measured by rate of growth of recurrent papillomas.
PGE2 increases papilloma cell proliferation while celecoxib reduces proliferation and increases apoptosis. PGE2 also increases HPV E6 and E7 transcription levels, through stimulation of the receptor EP4. Celecoxib inhibits activation of latent infection in the CRPV model. RRP patients’ LCs were less responsive to IL-36γ than controls, and PGE2 strongly suppressed IL-36γ-stimulated expression of select cytokines and chemokines. In the clinical trial, 36% of patients showed sustained clinical improvement, and 13% were in remission at the end of the study, but response was not significantly different from the placebo group. Overall prevalence of latency was 50% in responders, the same value we had previously determined for patients with active disease.
COX-2/PGE2 plays a major role in the pathophysiology of RRP. We propose that the therapeutic effects of celecoxib treatment in vivo in a subset of patients is due to suppressing latent activation, slowing papilloma growth and enhancing the local immune response.