Intraluminal antibodies to macrophage migration inhibitory factor decrease substance P induced inflammatory changes in the rat bladder and prostate.
OBJECTIVE
Noxious stimuli induce substance P (SP) secretion from nerve terminals, resulting in plasma extravasation, edema and hyperalgesia, commonly referred to as neurogenic inflammation. Since SP is a short-lived molecule, additional proinflammatory mediators maintain continued inflammation. The bladder contains stores of preformed macrophage migration inhibitory factor (MIF), a proinflammatory cytokine, which is released into the lumen in response to SP. MIF may act in an amplifying manner to maintain or increase inflammation. Inducing inflammatory changes with SP, while sequestering released luminal MIF with an antibody, tested this hypothesis.


METHODS
In anesthetized rats the ureters were cut to isolate the bladder and the bladder contents were replaced with saline or antiMIF antibody (5 or 15 microg/ml), immediately followed by systemic SP or saline. Changes in the expression of inflammatory cytokines, and histological changes in the bladder and prostate were evaluated 1 hour later.


RESULTS
: Targeted array analysis identified increases in proinflammatory gene expression in the bladder and prostate as a result of SP. SP induced changes in MIF, cyclooxygenase-2, nerve growth factor, c-fos and edema were decreased by intraluminal anti-MIF.


CONCLUSIONS
SP increased MIF amounts in the bladder lumen. Sequestering luminal MIF with an antiMIF antibody decreased SP induced inflammatory changes in the bladder and prostate, suggesting that MIF is involved in acute pelvic visceral neurogenic inflammation. These data indicate that MIF released from the bladder sustains or amplifies SP induced inflammation, a possibility that agrees with known MIF proinflammatory functions. These data continue to support our hypothesis that MIF is a new target for intervention in pelvic viscera inflammation.
Meyer-Siegler
Katherine L
KL
Bay Pines Veterans Affairs Medical Center, Research and Development Service, Bay Pines, Florida 33744, USA. Katherine.Siegler@med.va.gov
Vera
Pedro L
PL
D000818:Animals; D000906:Antibodies / Q000494:pharmacology*; D003556:Cystitis / Q000139:chemically induced / Q000473:pathology*; D016207:Cytokines / Q000378:metabolism; D007124:Immunoenzyme Techniques; D008263:Macrophage Migration-Inhibitory Factors / Q000037:antagonists & inhibitors* / Q000502:physiology; D008297:Male; D011467:Prostate / Q000473:pathology; D011472:Prostatitis / Q000139:chemically induced / Q000473:pathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013373:Substance P / Q000633:toxicity*; D001743:Urinary Bladder / Q000473:pathology
D000906:Antibodies; D016207:Cytokines; D008263:Macrophage Migration-Inhibitory Factors; D013373:Substance P