Interleukin-10 Anti-Inflammatory Response to<i>Borrelia burgdorferi</i>, the Agent of Lyme Disease: a Possible Role for Suppressors of Cytokine Signaling 1 and 3

Dennis, Vida A.; Jefferson, Ayanna; Singh, Shree R.; Ganapamo, Frédéric; Philipp, Mario T.

doi:10.1128/iai.00678-06

Cited by 48 publications

(53 citation statements)

References 70 publications

(89 reference statements)

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“…We have shown earlier that the PPE18 protein specifically interacts with the LRR 11-15 domain of TLR2 and activates early induction of IL-10 in macrophages (24). Several studies demonstrated that IL-10 enhances SOCS3 expression (27,78,79). Thus, it is possible that IL-10 is involved in the increased production of SOCS3 by PPE18 that in turn blocks proinflammatory cytokine induction in LPS-activated macrophages.…”

Section: Discussionmentioning

confidence: 99%

The PPE18 Protein of Mycobacterium tuberculosis Inhibits NF-κB/rel–Mediated Proinflammatory Cytokine Production by Upregulating and Phosphorylating Suppressor of Cytokine Signaling 3 Protein

Nair

Pandey

Mukhopadhyay

2011

The Journal of Immunology

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Mycobacterium tuberculosis bacteria are known to suppress proinflammatory cytokines like IL-12 and TNF-α for a biased Th2 response that favors a successful infection and its subsequent intracellular survival. However, the signaling pathways targeted by the bacilli to inhibit production of these cytokines are not fully understood. In this study, we demonstrate that the PPE18 protein of M. tuberculosis inhibits LPS-induced IL-12 and TNF-α production by blocking nuclear translocation of p50, p65 NF-κB, and c-rel transcription factors. We found that PPE18 upregulates the expression as well as tyrosine phosphorylation of suppressor of cytokine signaling 3 (SOCS3), and the phosphorylated SOCS3 physically interacts with IκBα–NF-κB/rel complex, inhibiting phosphorylation of IκBα at the serine 32/36 residues by IκB kinase-β, and thereby prevents nuclear translocation of the NF-κB/rel subunits in LPS-activated macrophages. Specific knockdown of SOCS3 by small interfering RNA enhanced IκBα phosphorylation, leading to increased nuclear levels of NF-κB/rel transcription factors vis-a-vis IL-12 p40 and TNF-α production in macrophages cotreated with PPE18 and LPS. The PPE18 protein did not affect the IκB kinase-β activity. Our study describes a novel mechanism by which phosphorylated SOCS3 inhibits NF-κB activation by masking the phosphorylation site of IκBα. Also, this study highlights the possible mechanisms by which the M. tuberculosis suppresses production of proinflammatory cytokines using PPE18.

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Section: Discussionmentioning

confidence: 99%

The PPE18 Protein of Mycobacterium tuberculosis Inhibits NF-κB/rel–Mediated Proinflammatory Cytokine Production by Upregulating and Phosphorylating Suppressor of Cytokine Signaling 3 Protein

Nair

Pandey

Mukhopadhyay

2011

The Journal of Immunology

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“…IL-10 was first described as a factor that could inhibit the production of proinflammatory cytokines by macrophages and other cell types (14)(15)(16)(17). In vitro, a number of cell types can produce IL-10 in response to stimulation by B. burgdorferi or B. burgdorferi antigens (24)(25)(26)(27)(28)(29)(30).…”

Section: Discussionmentioning

confidence: 99%

Adenoviral Delivery of Interleukin-10 Fails To Attenuate Experimental Lyme Disease

Brown

Lai²,

Callen³

et al. 2008

Infect Immun

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Production of interleukin-10 (IL-10) by C57BL/6 mice following infection with Borrelia burgdorferi has been proposed as a mechanism whereby resistance to the development of experimental Lyme arthritis is maintained. In the current study, we sought to determine the role of IL-10 during infection of arthritis-and carditissusceptible C3H mice. Infection of C3H IL-10 ؊/؊ mice led to increased joint swelling and arthritis severity scores over those of wild-type C3H mice. Measurement of B. burgdorferi numbers in joints or disseminated tissues indicated a more efficient clearance of spirochetes in the absence of IL-10, similar to that reported in C57BL/6 IL-10 ؊/؊ mice. However, in contrast to previous in vitro work, infection of C3H IL-10 ؊/؊ mice led to decreased in vivo expression of the cytokines KC, IL-1␤, IL-4, and IL-12p70 in the infected joints. Finally, adenoviral expression of IL-10 in the infected joints of C3H mice was unable to modulate the development of severe Lyme arthritis and had no effect on spirochete clearance or Borrelia-specific antibody production. Development of Lyme carditis appeared to be independent of modulation by IL-10. These results suggest that IL-10 limits the development of joint inflammation in both arthritis-resistant and -susceptible mouse strains infected with B. burgdorferi and that increased IL-10 production cannot rescue genetic susceptibility to development of pathology in this model.

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“…SOCS1 has been shown to be induced during infection with different mycobacterial species and Borrelia burgdorferi (22)(23)(24).…”

mentioning

confidence: 99%

SOCS-1 Protects against Chlamydia pneumoniae-Induced Lethal Inflammation but Hampers Effective Bacterial Clearance

Yang

Stark

Janik

et al. 2008

The Journal of Immunology

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Suppressor of cytokine signaling 1 (SOCS1) plays a major role in the inhibition of STAT1-mediated responses. STAT1-dependent responses are critical for resistance against infection with Chlamydia pneumoniae. We studied the regulation of expression of SOCS1 and SOCS3, and the role of SOCS1 during infection with C. pneumoniae in mice. Bone marrow-derived macrophages (BMM) and dendritic cells in vitro or lungs in vivo all showed enhanced STAT1-dependent SOCS1 mRNA accumulation after infection with C. pneumoniae. Infection-increased SOCS1 mRNA levels were dependent on IFN-αβ but not on IFN-γ. T or B cells were not required for SOCS1 mRNA accumulation in vivo. Infection-induced STAT1-phosphorylation occurred more rapidly in SOCS1−/− BMM. In agreement, expression of IFN-γ responsive genes, but not IL-1β, IL-6, or TNF-α were relatively increased in C. pneumoniae-infected SOCS1−/− BMM. Surprisingly, C. pneumoniae infection-induced IFN-α, IFN-β, and IFN-γ expression in BMM were attenuated by SOCS1. C. pneumoniae infection of RAG1−/−/SOCS1−/− mice induced a rapid lethal inflammation, accompanied by diminished pulmonary bacterial load and increased levels of iNOS and IDO but not IL-1β, IL-6, or TNF-α mRNA. In summary, C. pneumoniae infection induces a STAT1, IFN-αβ-dependent and IFN-γ independent SOCS1 mRNA accumulation. Presence of SOCS1 controls the infection-induced lethal inflammatory disease but impairs the bacterial control.

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Interleukin-10 Anti-Inflammatory Response toBorrelia burgdorferi, the Agent of Lyme Disease: a Possible Role for Suppressors of Cytokine Signaling 1 and 3

Cited by 48 publications

References 70 publications

The PPE18 Protein of Mycobacterium tuberculosis Inhibits NF-κB/rel–Mediated Proinflammatory Cytokine Production by Upregulating and Phosphorylating Suppressor of Cytokine Signaling 3 Protein

The PPE18 Protein of Mycobacterium tuberculosis Inhibits NF-κB/rel–Mediated Proinflammatory Cytokine Production by Upregulating and Phosphorylating Suppressor of Cytokine Signaling 3 Protein

Adenoviral Delivery of Interleukin-10 Fails To Attenuate Experimental Lyme Disease

SOCS-1 Protects against Chlamydia pneumoniae-Induced Lethal Inflammation but Hampers Effective Bacterial Clearance

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