Does Inhibition of Tumor Necrosis Factor Alpha Affect Chlamydial Genital Tract Infection in Mice and Guinea Pigs?

Darville, Toni; Andrews, Charles W.; Rank, Roger G.

doi:10.1128/iai.68.9.5299-5305.2000

Cited by 37 publications

(30 citation statements)

References 37 publications

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“…Increased neutrophil influx into the lower genital tracts of C57 and BALB/c mice paralleled the high TNF-␣ and IL-1␤ responses of these mice during the first week of infection. However, our previous data on depletion of TNF-␣ indicate that neutrophil chemotaxis is effectively induced in its absence (8). Moreover, the largest numbers of neutrophils were seen in the lower genital tract of the BALB/c strain during the first week of infection and were associated with significantly increased levels of MIP-2.…”

Section: Discussionmentioning

confidence: 99%

Early Local Cytokine Profiles in Strains of Mice with Different Outcomes from Chlamydial Genital Tract Infection

et al. 2001

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In this study, we expand on the examination of genetically determined differences in host responses that correlate with clearance of Chlamydia trachomatis from the genital tract. We infected C57BL/6, BALB/c, and C3H/HeN mice with the mouse pneumonitis agent of C. trachomatis (MoPn). C57BL/6 mice had the shortest course of infection (22 days) and the lowest incidence of severe hydrosalpinx. BALB/c mice also had a short course of infection (25 days), but all developed hydrosalpinx. C3H/HeN mice had the longest course of infection (38 days), and all developed severe hydrosalpinx. Determination of local cytokine responses by enzyme-linked immunosorbent assay (ELISA) of genital tract secretions revealed that the levels of the proinflammatory cytokines tumor necrosis factor-alpha (TNF-␣) and interleukin-1␤ (IL-1␤) were significantly increased in the C57BL/6 and BALB/c strains compared to those in the C3H/HeN strain whereas the level of IL-6 was not different. The level of the neutrophil chemokine macrophage inflammatory protein 2 (MIP-2) was increased during the first week of infection in all three strains but was significantly higher in the BALB/c strain, the strain with the most rapid influx of neutrophils into the genital tract. Prolonged detection of MIP-2 in C3H/HeN mice was associated with a protracted presence of neutrophils in the genital tract. Early increases in the levels of the proinflammatory cytokines TNF-␣ and IL-1␤ are associated with earlier eradication of infection in the C57BL/6 and BALB/c strains than in the C3H/HeN strain. Increased levels of MIP-2 and neutrophils in BALB/c and C3H/HeN mice relative to C57BL/6 mice suggest that these responses may contribute to pathology.

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Section: Discussionmentioning

confidence: 99%

Early Local Cytokine Profiles in Strains of Mice with Different Outcomes from Chlamydial Genital Tract Infection

et al. 2001

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“…Tumor necrosis factor alpha and interleukin 1␤ (IL-1␤) levels are markedly elevated in the C57BL/6 mice relative to C3H/ HeN mice, and there are correlative data related to a prolonged presence of neutrophils and coincident increases in chemokine macrophage inflammatory protein 2 in the susceptible strains (8,9). Apoptosis and Toll-like receptor 2 signaling have both also been implied in initiating and regulating inflammatory damage in this model (10,32).…”

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confidence: 89%

Expression of Matrix Metalloproteinases Subsequent to UrogenitalChlamydia muridarumInfection of Mice

et al. 2005

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The central hypothesis of this study was that matrix metalloproteinases (MMPs) would be enhanced following murine chlamydial infection and that their expression would vary in mouse strains that differ in their susceptibility to chronic chlamydia-induced disease. To address this hypothesis, female C3H/HeN and C57BL/6 mice were infected intravaginally with Chlamydia muridarum. Uterine and oviduct tissues were assessed for transcription of MMP genes and their tissue inhibitors. An increased activity of MMP genes relative to preinfection tissues was observed in the C3H/HeN mice when compared to C57BL/6 mice. Using gelatin zymography, we detected constitutive MMP-2 activity in both strains of mice but an increase in MMP-9. Casein zymography indicated the presence of two elastase-like activities consistent with MMP-12 and possibly MMP-7. Western blotting and antigen capture enzyme-linked immunoassay also confirmed an increase in MMP-9 but constitutive MMP-2 expression subsequent to the infection in both strains of mice. In C57BL/6 mice, MMP-9 was present in monomer and dimer form throughout the 56-day monitoring period. C3H/HeN mice produced dimeric MMP-9, but increases in the monomer form were also observed through day 14. Post-translational modification of MMP-9 between the two strains also differed. Immunohistochemistry revealed neutrophils as a prominent source for MMP-9 in both strains of mice. We conclude that differences in the relative expression and activity of MMPs, particularly MMP-9, occur in mice differing in their susceptibility to the development of chronic chlamydial disease. These differences may account for disparate outcomes with regard to chronic sequelae of the disease.

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“…We have recently reported a role for iNOS in protection from chronic chlamydial disease in mice (32). In addition, Darville et al have shown a positive correlation between the production of tumor necrosis factor alpha early in infection and resistance to disease (11). In contrast, increased and sustained macrophage inflammatory protein 2 production and the corresponding neutrophil influx were associated with susceptibility to disease (12).…”

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Role for Inducible Nitric Oxide Synthase in Protection from ChronicChlamydia trachomatisUrogenital Disease in Mice and Its Regulation by Oxygen Free Radicals

et al. 2001

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It has been previously reported that although inducible nitric oxide synthase (iNOS) gene knockout (NOS2؊/؊ ) mice resolve Chlamydia trachomatis genital infection, the production of reactive nitrogen species (RNS) via iNOS protects a significant proportion of mice from hydrosalpinx formation and infertility. We now report that higher in vivo RNS production correlates with mouse strain-related innate resistance to hydrosalpinx formation. We also show that mice with a deletion of a key component of phagocyte NADPH oxidase (p47 phox؊/؊ ) resolve infection, produce greater amounts of RNS in vivo, and sustain lower rates of hydrosalpinx formation than both wild-type (WT) NOS2 ؉/؉ and NOS2 ؊/؊ controls. When we induced an in vivo chemical block in iNOS activity in p47 phox؊/؊ mice using N G -monomethyl-L-arginine (L-NMMA), a large proportion of these mice eventually succumbed to opportunistic infections, but not before they resolved their chlamydial infections. Interestingly, when compared to WT and untreated p47 phox؊/؊ controls, L-NMMA-treated p47 phox؊/؊ mice resolved their infections more rapidly. However, L-NMMA-treated p47 phox؊/؊ mice lost resistance to chronic chlamydial disease, as evidenced by an increased rate of hydrosalpinx formation that was comparable to that for NOS2 ؊/؊ mice. We conclude that phagocyte oxidase-derived reactive oxygen species (ROS) regulate RNS during chlamydial urogenital infection in the mouse. We further conclude that while neither phagocyte oxidase-derived ROS nor iNOS-derived RNS are essential for resolution of infection, RNS protect from chronic chlamydial disease in this model.

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Does Inhibition of Tumor Necrosis Factor Alpha Affect Chlamydial Genital Tract Infection in Mice and Guinea Pigs?

Cited by 37 publications

References 37 publications

Early Local Cytokine Profiles in Strains of Mice with Different Outcomes from Chlamydial Genital Tract Infection

Early Local Cytokine Profiles in Strains of Mice with Different Outcomes from Chlamydial Genital Tract Infection

Expression of Matrix Metalloproteinases Subsequent to UrogenitalChlamydia muridarumInfection of Mice

Role for Inducible Nitric Oxide Synthase in Protection from ChronicChlamydia trachomatisUrogenital Disease in Mice and Its Regulation by Oxygen Free Radicals

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