Neutrophil involvement in effects of diethylstilbestrol and strontium 89 on macrophage activation by propionibacterium acnes

Abstract

We have recently demonstrated that diethylstilbestrol (DES) significantly suppresses macrophage (Mφ) activation by Propionibacterium acnes. Because the initial activation of Mφ by P. acnes appears to involve the close interaction of the killed bacteria with inflammatory neutrophils (PMN) and resident Mφ in the peritoneal cavity, we investigated whether the DES inhibition of Mφ activation was associated with inhibition of the PMN response. Our data demonstrate that treatment of mice with DES did not interfere with the acute inflammatory peritoneal PMN influx 5 h after P. acnes injection. DES treatment also did not affect development of the early (day 4) tumor cytotoxic activity of P. acnes activated Mφ; this Mφ activity has been shown to be mediated by the acute PMN influx, DES treatment, however, did reduce Mφ activation as evidenced by alterations in other markers typically associated with Mφ activation by P. acnes, including the characteristic reductions in alkaline phosphodieterase (APD) ectoenzyme activity and total RNA synthesis, as well as the characteristic persistence of the peritoneal PMN response seen on days 4 and 7 after P. acnes injection. In addition, Mφ activity 7 days after P. acnes injection was inhibited in DES treated mice, as evidenced by reduced antitumor activity,and alteration of the markers mentioned above. As a second approach to elucidate the involvement of the acute and persistent PMN response in the Mθ activation process, we depleted mice of circulating PMN by treatment of mice with 89Sr before administration of P. acnes. This inhibited the inflammatory peritoneal PMN response 5 h, 4 days or 7 dyas after P. acnes injection and abrogated the Mφ activating capability of P. acnes. These results demonstrate that DES interferes less with the early phases of the P. acnes induced Mφ activation process than with the maintenance of Mφ activation. The data provide additional support for the importance of the acute PMN inflammatory response in at least early phases of Mφ activation by P. acnes. The possibility exists that after the administration of an immunomodulator such as P. acnes, Mφ activation is controlled by different, independently acting cells or mediators that act sequentially.