MIF mediates bladder pain, not inflammation, in cyclophosphamide cystitis.

ABSTRACT

Macrophage migration inhibitory factor (MIF), a proinflammatory mediator, is recognized as a player in inflammatory and neuropathic pain. Cyclophosphamide (CYP) results in bladder inflammation and pain and it's a frequently used animal model of interstitial cystitis/bladder pain syndrome (IC/BPS). Because pretreatment with a MIF inhibitor (ISO-1) prevented both CYP-induced bladder pain and inflammation we used genetic MIF knockout (KO) mice to further investigate MIF's role in CYP-induced bladder pain and inflammation. Abdominal mechanical threshold measured bladder pain induced by CYP in wild type (WT) and MIF KO mice at several time points (0-48 hours). End-point (48 hours) changes in micturition parameters and histological signs of bladder inflammation were also evaluated. Abdominal mechanical hypersensitivity developed within 4 hours after CYP injection (and lasted for the entire observation period 48 hours) in WT mice. MIF KO mice, on the other hand, did not develop abdominal mechanical hypersensitivity suggesting that MIF is a pivotal molecule in mediating CYP-induced bladder pain. Both WT and MIF KO mice treated with CYP showed histological signs of marked bladder inflammation and showed a significant decrease in micturition volume and increase in frequency. Since both changes were blocked in MIF KO mice by pretreatment with a MIF inhibitor (ISO-1) it is likely these are non-specific effects of ISO-1. MIF mediates CYP-induced bladder pain but not CYP-induced bladder inflammation. The locus of effect (bladder) or central (spinal) for MIF mediation of bladder pain remains to be determined.