Roles of Interleukin-12 and Gamma Interferon in Murine<i>Chlamydia pneumoniae</i>Infection

Geng, Yuemei; Berencsi, Klára; Gyulai, Z.; Vályi-Nagy, Tibor; Gönczöl, Éva; Trinchieri, Giorgio

doi:10.1128/iai.68.4.2245-2253.2000

Cited by 55 publications

(29 citation statements)

References 57 publications

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“…Our studies demonstrate that both live C. pneumoniae and acellular chlamydial components not only induce TNF, IL-1␤, and IL-6 (19), but are also a strong stimulus of IFN-␥ production, and this may be a crucial step in the atherogenic role of Chlamydia. These results are supported by other studies reporting IFN-␥ production by C. pneumoniae infection (20,21). However, the finding that even acellular chlamydial components strongly stimulate IFN-␥ production is important in the view of the reports suggesting that mainly the chlamydial Ags and not the live microorganisms are present in the atheromatous plaques in humans (22,23).…”

Section: Discussionsupporting

confidence: 76%

Chlamydia pneumoniae Stimulates IFN-γ Synthesis through MyD88-Dependent, TLR2- and TLR4-Independent Induction of IL-18 Release

Netea

Kullberg

Jacobs

et al. 2004

The Journal of Immunology

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Recent studies suggest that inflammation plays a central role in the pathogenesis of atherosclerosis, and IFN-γ is a prominent proinflammatory mediator in this context. However, it is unclear what stimuli are responsible for initial stimulation of IFN-γ synthesis in the vessel wall. In the present study, we demonstrate that Chlamydia pneumoniae is an important stimulus for IFN-γ synthesis, and this production depends on release of endogenous IL-18, IL-12, and IL-1, but not of TNF. The production of the proinflammatory cytokines TNF and IL-1β from PBMC by sonicated C. pneumoniae was mediated through TLR2-dependent pathways. In contrast, C. pneumoniae stimulated the production of IL-18 through MyD88-dependent, TLR2-, TLR4-, and CD14-independent pathways, mediated by posttranscriptional mechanisms not involving de novo protein synthesis. In conclusion, C. pneumoniae is a potent stimulus of IFN-γ production, in addition to the proinflammatory cytokines TNF and IL-1β, which may contribute to its proatherogenic effects. Most interestingly, C. pneumoniae is also a potent inducer of IL-18 production through pathways independent of TLR2 and TLR4.

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Section: Discussionsupporting

confidence: 76%

Chlamydia pneumoniae Stimulates IFN-γ Synthesis through MyD88-Dependent, TLR2- and TLR4-Independent Induction of IL-18 Release

Netea

Kullberg

Jacobs

et al. 2004

The Journal of Immunology

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“…IFN-c and IL-12p40 are crucial to control chlamydial replication in vivo, since the chlamydial load is higher in mice deficient for the IFN-c receptor or IL-12p40 or in mice treated with an IL-12p40 antibody [23][24][25]. It was, therefore, surprising that TLR2 -/-ÂTLR4 d/d mice succumbed to infection with C. pneumoniae, although their pulmonary IL-12p40 and IFN-c levels were at least as high as in WT mice.…”

Section: Discussionmentioning

confidence: 99%

Differential involvement of TLR2 and TLR4 in host survival during pulmonary infection with Chlamydia pneumoniae

Rodríguez

Wantia

Fend³

et al. 2006

Eur J Immunol

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The relevance of TLR2 and TLR4 for recognizing Chlamydia pneumoniae in vivo during pulmonary infection and to survive the infection was explored. We found that early immune responses triggered by C. pneumoniae partially depended on TLR2, but not on TLR4. The chemokines MIP-2 and MIP-1a were not induced, while IL-12p40 levels were higher in TLR2 -/-mice compared to wild-type mice. Secretion of TNF, keratinocytederived chemokine and monocyte chemoattractant protein-1 was attenuated in TLR2 -/-mice, while IFN-c was increased as in wild-type mice. The pulmonary cyto-and chemokine response of TLR2 -/-ÂTLR4 d/d was similar to TLR2 -/-mice. TLR2 -/-and TLR2 -/-ÂTLR4 d/d mice also attracted fewer polymorphonuclear neutrophils into the lung, while TLR4 d/d mice recruited them. Attenuated recruitment of polymorphonuclear neutrophils correlated with reduced weight loss in TLR2 -/-and TLR2 -/-ÂTLR4 d/d mice and a lower chlamydial burden 3 days post infection. At 9 days post infection, TLR2 -/-and TLR2 -/-ÂTLR4 d/d mice produced cyto-and chemokines as efficiently as wild-type mice, indicating that the involvement of TLR in inflammation varies over time. All TLR2 -/-ÂTLR4 d/d mice succumbed to the infection, while about 50% of TLR2 -/-mice died. Taken together, the function of TLR2 and TLR4 is required to survive pulmonary infection with C. pneumoniae.

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“…Also, our experiments show that on day 6 postinfection, TNF, IFN-␥, KC, and MCP-1 are secreted MyD88 independently. IL-12 participates in the control of C. pneumoniae replication in vivo, because anti IL-12p40 treatment results in higher chlamydial titers, but less severe pathological changes within the lung of infected mice (33). From the adaptors identified to date, only TICAM-1 (Toll-IL-7R domain-containing adaptor-inducing IFN-␤) appears to operate MyD88 independently (15,18).…”

Section: Figure 5 Depletion Of Gr1mentioning

confidence: 99%

Polymorphonuclear Neutrophils Improve Replication ofChlamydia pneumoniaeIn Vivo upon MyD88-Dependent Attraction

Rodríguez

Fend

Jennen

et al. 2005

The Journal of Immunology

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Chlamydia pneumoniae, an obligate intracellular bacterium, causes pneumonia in humans and mice. In this study, we show that GR1+/CD45+ polymorphonuclear neutrophils (PMN) surprisingly increase the bacterial load of C. pneumoniae in vivo. Upon intranasal infection of wild-type mice, the lung weight is increased; the cytokines TNF, IL-12p40, and IFN-γ, as well as the chemokines keratinocyte-derived chemokine, MCP-1, and MIP-2 are secreted; and GR1+/CD45+ PMN are recruited into lungs 3 days postinfection. In contrast, in infected MyD88-deficient mice, which lack a key adaptor molecule in the signaling cascade of TLRs and IL-1R family members, the increase of the lung weight is attenuated, and from the analyzed cyto- and chemokines, only IL-12p40 is detectable. Upon infection, almost no influx of inflammatory cells into lungs of MyD88-deficient mice can be observed. Six days postinfection, however, MyD88-deficient mice were able to produce TNF, IFN-γ, keratinocyte-derived chemokine, and MCP-1 in amounts similar to wild-type mice, but failed to secrete IL-12p40 and MIP-2. At this time point, the infection increased the lung weight to a level similar to wild-type mice. Curiously, the chlamydial burden in MyD88-deficient mice 3 days postinfection is lower than in wild-type mice, a finding that can be reproduced in wild-type mice by depletion of GR1+ cells. In analyzing how PMN influence the chlamydial burden in vivo, we find that PMN are infected and enhance the replication of C. pneumoniae in epithelial cells. Thus, the lower chlamydial burden in MyD88-deficient mice can be explained by the failure to recruit PMN.

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Roles of Interleukin-12 and Gamma Interferon in MurineChlamydia pneumoniaeInfection

Cited by 55 publications

References 57 publications

Chlamydia pneumoniae Stimulates IFN-γ Synthesis through MyD88-Dependent, TLR2- and TLR4-Independent Induction of IL-18 Release

Chlamydia pneumoniae Stimulates IFN-γ Synthesis through MyD88-Dependent, TLR2- and TLR4-Independent Induction of IL-18 Release

Differential involvement of TLR2 and TLR4 in host survival during pulmonary infection with Chlamydia pneumoniae

Polymorphonuclear Neutrophils Improve Replication ofChlamydia pneumoniaeIn Vivo upon MyD88-Dependent Attraction

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