Inhibition of macrophage migration inhibitory factor decreases proliferation and cytokine expression in bladder cancer cells.
BACKGROUND
The importance of various inflammatory cytokines in maintaining tumor cell growth and viability is well established. Increased expression of the proinflammatory cytokine macrophage migration inhibitory factor (MIF) has previously been associated with various types of adenocarcinoma.


METHODS
MIF IHC was used to localize MIF in human bladder tissue. ELISA and Western blot analysis determined the synthesis and secretion of MIF by human bladder transitional cell carcinoma cells. The effects of MIF inhibitors (high molecular weight hyaluronate (HA), anti-MIF antibody or MIF anti-sense) on cell growth and cytokine expression were analyzed.


RESULTS
Human bladder cancer cells (HT-1376) secrete detectable amounts of MIF protein. Treatment with HA, anti-MIF antibody and MIF anti-sense reduced HT-1376 cell proliferation, MIF protein secretion, MIF gene expression and secreted inflammatory cytokines. Our evidence suggests MIF interacts with the invariant chain, CD74 and the major cell surface receptor for HA, CD44.


CONCLUSIONS
This study is the first to report MIF expression in the human bladder and these findings support a role for MIF in tumor cell proliferation. Since MIF participates in the inflammatory response and bladder cancer is associated with chronic inflammatory conditions, these new findings suggest that neutralizing bladder tumor MIF may serve as a novel therapeutic treatment for bladder carcinoma.
Meyer-Siegler
Katherine L
KL
Research & Development Service (151), Bay Pines VA Medical Center, Bay Pines, FL 33744, USA. Katherine.Siegler@med.va.gov
Leifheit
Erica C
EC
Vera
Pedro L
PL
D015703:Antigens, CD / Q000378:metabolism; D051925:CD79 Antigens; D002455:Cell Division / Q000235:genetics; D016207:Cytokines / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D006820:Hyaluronic Acid / Q000494:pharmacology; D007375:Interleukin-1 / Q000378:metabolism; D008263:Macrophage Migration-Inhibitory Factors / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D001743:Urinary Bladder / Q000737:chemistry; D001749:Urinary Bladder Neoplasms / Q000378:metabolism* / Q000473:pathology*
D015703:Antigens, CD; D051925:CD79 Antigens; C497881:CD79A protein, human; D016207:Cytokines; D018960:Hyaluronan Receptors; D007375:Interleukin-1; D008263:Macrophage Migration-Inhibitory Factors; D011947:Receptors, Antigen, B-Cell; D014409:Tumor Necrosis Factor-alpha; D006820:Hyaluronic Acid