A novel expression of macrophage derived chemokine in human bladder cancer

Successful bacillus Calmette-Guerin (BCG) immunotherapy for bladder cancer is associated with proper induction of T helper (Th)1 immunity. Unfortunately, 30% to 40% of bladder tumors never respond to BCG. We sought evidence of antagonistic Th2 chemokine production by bladder tumors as a potential cause of BCG nonresponsiveness.

Expression of interferon-gamma inducible protein-10 (IP-10), a Th1 chemokine, and macrophage derived chemokine (MDC), a Th2 chemokine, was examined in 9 clinical bladder tumor specimens and 7 human bladder cancer lines by sandwich enzyme-linked immunosorbent assay, immunohistochemistry and immunofluorescence. Regulation of these chemokine expressions in the human RT4 bladder cancer line was also explored by reverse transcription-polymerase chain reaction and electrophoretic mobility shift assay.

Eight of 9 clinical specimens expressed IP-10 and 5 expressed MDC. However, of 7 cancer lines only 1 low grade line (RT4) expressed IP-10 and MDC, and 1 high grade line (T24) expressed IP-10. Histological staining demonstrated MDC and IP-10 expression in human bladder tumors. Interestingly interferon-gamma and tumor necrosis factor-alpha up-regulated and synergized the expression of these 2 chemokines in RT4 cells. Such positive effects appeared to be mediated by nuclear factor-kappaB but not by the AP-1 signaling pathway.

These results indicate that certain bladder tumors produce the Th2 chemokine MDC, which may antagonize the local Th1 environment induced by BCG. MDC production by bladder tumors appears to be mediated by signals distinct from those identified in macrophages.