Does inhibition of tumor necrosis factor alpha affect chlamydial genital tract infection in mice and guinea pigs

The role of tumor necrosis factor alpha (TNF-a) in host defense against chlamydial infection remains unclear. In order to further evaluate the relevance of TNF-a to host resistance in chlamydial genital tract infection, we examined the effect of local inhibition of the TNF-a response in normal C57 mice and in interferon gamma gene-deficient C57 mice infected intravaginally with the mouse pneumonitis agent of Chlamydia trachomatis. Since the guinea pig model of female genital tract infection more closely approximates the human in terms of ascending infection and development of pathology, we also examined the effect of local inhibition of the TNF-a response in guinea pigs infected intravaginally with the guinea pig strain of Chlamydia psittaci .W e successfully blocked the early TNF-a response in the respective animal models. This blockade had no effect on the numbers of organisms isolated from the genital tract during the time of TNF-a inhibition in mice or guinea pigs. Analysis of interleukin-1b, macrophage inflammatory protein-2, and granulocyte macrophage-colony stimulating factor in the mouse model revealed that blockade of the TNF-a response did not alter the release of these proinflammatory proteins. Yet, in TNF-a-depleted mice, increased numbers of neutrophils were detected in the genital tract, and, in TNF-a-depleted guinea pigs, increased numbers of neutrophils as well as infiltrating lymphocytes were seen in the endocervix. Blockade of TNF-a does not affect the level of infection in mice or guinea pigs, but it may decrease TNF-a-induced apoptosis of infiltrating inflammatory cells. Tumor necrosis factor alpha (TNF-a) is a proinflammatory cytokine released primarily from monocytes and macrophages upon invasion of the host by a wide variety of pathogens. It contributes in various ways to defense against pathogenic agents. In the late 1980s, Manor and Sarov reported that human monocyte-derived macrophages inhibit growth of Chlamydia trachomatis (L2/4434/Bu) in human laryngeal carcinoma cells (HEp-2 cells), and this inhibition is reduced by the addition of anti-TNF-a antibodies (17). Further, Shomer-Avni et al. reported a direct inhibitory effect of human recombinant TNF-a on the in vitro growth of C. trachomatis in HEp-2 cells (34). However, recent work published by Perry and colleagues reported that TNF-a has no effect on the in vitro growth of the human strains of C. trachomatis serovar D or L2 or the mouse pneumonitis agent of C. trachomatis (MoPn) when murine intestinal epithelial cell lines are used for culture (25). These different conclusions may simply indicate that TNF-a has different effects on chlamydiae in human versus rodent cells in vitro, but they point out that further investigations of the role of TNF-a in host defense against chlamydiae are needed. There is evidence that TNF-a plays a role in vivo in host defense against chlamydiae. In a murine model of chlamydial pneumonia, Williams et al. demonstrated that exogenous administration of anti-TNF-a antibody significantly accelerated mortality and caused an increase in MoPn counts in the lung (39). As regards genital tract infection, mice genetically deficient in the p55 type I receptor for TNF-a have a statistically significant delay in clearance of MoPn and of human serovar D from the genital tract (25). As no direct inhibitory effect of TNF-a was determined in vitro in this study, the investigators proposed that the delay in clearance was due to indirect effects of TNF-a on local effectors of host defense. We reported the detection of high levels of TNF-a in C57BL/6 (C57) mice infected with MoPn or human serovar E during the first week of primary infection (10). Significantly lower levels of TNF-a were found in C3H/HeN mice, and the C3H strain was found to have a prolonged course of infection and increased oviduct pathology compared to the C57 strain, suggesting that increased TNF-a levels enhance host defense in the C57 strain. Further, C57 mice deficient in gamma interferon (IFN-g) continue to exhibit near eradication of MoPn from the genital tract mucosa (9, 23). The effector mechanism responsible for this IFN-g-independent clearance of MoPn is unknown. Although studies have not shown a compensatory increase in mRNA levels of TNF-a in IFN-g gene-deficient mice, local protein levels of TNF-a have not been reported. Since TNF-a biosynthesis is largely controlled at a translational level, a significant increase in secretion of the protein may occur without detection of a significant increase in transcription of the TNF-a gene (15).