Intravesical bacille Calmette-Guerin induces the antiangiogenic chemokine interferon-inducible protein 10

Abstract

Objectives. Intravesical bacille Calmette-Guerin (BCG) induces a variety of cytokines into the urine of patients with superficial transitional cell carcinoma (TCC) of the bladder, Recent data have shown that some cytokines have antiangiogenic activitY. We sought to determine whether the potently antiangiogenic chemokine interferon-inducible protein 10 (IP-10) and its inducing antiangiogenic cytokines, interferon-gamma (IFN-γ) and interleukin- 12 (IL-12), are increased during intravesical BCG immunotherapy of bladder TCC. Methods. Voided urine samples were collected sequentially from 8 patients before and after each weekly intravesical BCG treatment and from 4 patients receiving maintenance BCG treatments. The urinary output of IP-10, IFN-γ, and IL-12 over 12 post-treatment hours was assessed by enzyme-linked immunosorbent assay. In vitro BCG and cytokine stimulations of human TCC and primary endothelial cell lines were also performed, and their supernatants were studied for IP-10. Results. In all cases after intravesical BCG, patient urine was found to contain significant elevations of IP-10. Urinary IFN-γ and IL-12 levels also increased in similar patterns after intravesical BCG. The peak weekly cytokine response per patient usually occurred between the fourth and sixth treatment for IFN-γ and IP-10, but was less predictable for IL-12. Human TCC and endothelial cell lines were able to secrete IP-10 in response to BCG or interferon stimulation in vitro. Conclusions. Our small series demonstrates that IP-10 and its inducing cytokines are elevated in response to intravesical BCG. These data suggest that, in addition to a cellular immune response, BCG may induce a cytokine-mediated antiangiogenic environment that aids in inhibiting future tumor growth and progression.