RT Journal Article
SR Electronic
T1 IPSE, a parasite-derived host immunomodulatory protein, is a promising therapeutic for hemorrhagic cystitis
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 400424
DO 10.1101/400424
A1 Rebecca S. Zee
A1 Evaristus C. Mbanefo
A1 Loc H. Le
A1 Luke F. Pennington
A1 Justin Odegaard
A1 Theodore S. Jardetzky
A1 Abdulaziz Alouffi
A1 Jude Akinwale
A1 Franco H. Falcone
A1 Michael H. Hsieh
YR 2018
UL http://biorxiv.org/content/early/2018/08/25/400424.abstract
AB Chemotherapy-induced hemorrhagic cystitis is characterized by bladder pain and voiding dysfunction caused by hemorrhage and inflammation. Of currently available therapies, prophylactic 2-mercaptoethanesulfonic acid (MESNA) has limited efficacy and cannot treat pre-existing lesions. Therefore, novel therapeutic options to treat hemorrhagic cystitis are needed. We previously reported that systemic administration of the Schistosomiasis haematobium-derived protein H-IPSEH06 (IL-4-inducing principle from Schistosoma mansoni eggs), is superior to 3 doses of MESNA in alleviating hemorrhagic cystitis. Based on prior reports by others on S. mansoni IPSE and additional work by our group, we reasoned that H-IPSEH06 mediates its effects on hemorrhagic cystitis by binding IgE on basophils and inducing IL-4 expression, promoting urothelial proliferation, and translocating to the nucleus to modulate expression of genes implicated in relieving bladder dysfunction. We speculated that local bladder injection of the S. haematobium IPSE ortholog IPSEH03, hereafter called H-IPSEH03, might be more efficacious in preventing hemorrhagic cystitis compared to systemic administration of IPSEH06. We demonstrate herein that H-IPSEH03 is a promising therapeutic for the treatment of voiding dysfunction and bladder pain in hemorrhagic cystitis. Namely, it attenuates ifosfamide-induced increases in bladder wet weight in an IL-4-dependent fashion. H-IPSEH03 relieves hemorrhagic cystitis-associated allodynia. Finally, H-IPSEH03 drives increased urothelial cell proliferation. This indicates that IPSE induces bladder healing mechanisms, which suggests that it may be a novel non-opioid analgesic to treat bladder pain syndromes.AbbrevationsCFSE5-(and 6)-Carboxyfluorescein diacetate succinimidyl esterIPSEInterleukin-4 inducing principle from Schistosoma mansoni eggsMESNA2-mercaptoethanesulfonic acidNLSNuclearlocalization sequence