Role of endogenous IL-10 in LPS-induced STAT3 activation and IL-1 receptor antagonist gene expression

Carl, Virginia S.; Gautam, Jitendra; Comeau, Laurey; Smith, Michael F.

doi:10.1189/jlb.1003526

Cited by 46 publications

(43 citation statements)

References 37 publications

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“…Thus, transferred B cells may indeed modulate the functions of innate immune cells in lung and spleen to also promote regulatory dendritic cells or macrophages capable of producing IL-10 and other innate immune regulators (reviewed in references 85 and 86). This finding would be consistent with the concomitant upregulation of IL-10, IL-27, and also IL1Ra observed in B cell-transferred IFrag Ϫ/Ϫ mice (80,87,88). In support of this, we found in preliminary experiments that coculture of B cells with pulmonary CD11b…”

Section: Discussionsupporting

confidence: 79%

B Cells Modulate Systemic Responses to Pneumocystis murina Lung Infection and Protect On-Demand Hematopoiesis via T Cell-Independent Innate Mechanisms when Type I Interferon Signaling Is Absent

et al. 2015

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HIV infection results in a complex immunodeficiency due to loss of CD4؉ T cells, impaired type I interferon (IFN) responses, and B cell dysfunctions causing susceptibility to opportunistic infections such as Pneumocystis murina pneumonia and unexplained comorbidities, including bone marrow dysfunctions. Type I IFNs and B cells critically contribute to immunity to Pneumocystis lung infection. We recently also identified B cells as supporters of on-demand hematopoiesis following Pneumocystis infection that would otherwise be hampered due to systemic immune effects initiated in the context of a defective type I IFN system. While studying the role of type I IFNs in immunity to Pneumocystis infection, we discovered that mice lacking both lymphocytes and type I IFN receptor (IFrag Pneumocystis is a ubiquitous extracellular pulmonary fungal pathogen with strict species specificity. It is likely contracted via airborne transmission from often transiently infected individuals and commonly causes few or unspecific symptoms in otherwise healthy individuals leading to immunity (reviewed in references 1 and 2). However, Pneumocystis can cause severe and progressive interstitial pneumonia in patients with impaired acquired immunity with mortality rates up to 60% (3). While the total number of functional CD4 ϩ T cells critically determines increased susceptibility to Pneumocystis lung infection, patients with B cell defects are also at risk. In this regard, Pneumocystis pneumonia (PCP) is an AIDSdefining condition during HIV disease progression and commonly occurs when CD4 ϩ T cell counts drop below 200 cells/l (4). Furthermore, immune suppressive and cell ablative therapy following solid-organ transplantation, autoimmunity, or cancer treatment reduce CD4 ϩ T cell and/or B cell numbers and impair functions in non-HIV patients (reviewed in references 5 and 6). Drug regimens that predispose to severe Pneumocystis infections include high-dose glucocorticoid and B cell ablative treatments with rituximab (7-11). In addition, low-grade Pneumocystis infection is found in patients with potentially subtle immune suppressions such as young infants, HIV-positive patients receiving HAART (highly active antiretroviral therapy), or patients receiving low-dose and inhaled glucocorticoids (12)(13)(14). This can promote bronchial hyperreactivity, is associated with sudden infant death syndrome (SIDS) and exacerbation of chronic obstructive lung diseases (15)(16)(17)(18)(19).Pneumocystis colonization also intensifies signs of systemic inflammation (20, 21). Thus, Pneumocystis may act as a profound comorbidity factor that may also enhance secondary systemic disease manifestations associated with chronic pulmonary diseases and HIV infection such as osteoporosis or bone marrow dysfunctions (22-28). Immunity to Pneumocystis requires the presence of functional CD4 ϩ T cells to stimulate antigen-specific immune globulin production by B cells and macrophage-mediated phagocytosis (4,(29)(30)(31)(32)(33)(34)(35)(36)(37)(38). In addition, early innate t...

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Section: Discussionsupporting

confidence: 79%

B Cells Modulate Systemic Responses to Pneumocystis murina Lung Infection and Protect On-Demand Hematopoiesis via T Cell-Independent Innate Mechanisms when Type I Interferon Signaling Is Absent

et al. 2015

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“…An example of this could be the transcription factor STAT3, which has been shown to be activated by IL-10 [38]. Endogenous IL-10 in LPS stimulation of macrophages (RAW264.7) [39] forms the IL-10-IL10R complex that initiates phosphorylation of cytosolic STAT3, followed by its dimerization and translocation into the nucleus. The STAT3 dimer binds to the DNA response element and triggers transcription of IL-10 ( Figure S1).…”

Section: Figurementioning

confidence: 99%

Mathematical Modeling of Pro- and Anti-Inflammatory Signaling in Macrophages

et al. 2014

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Inflammation is a beneficial mechanism that is usually triggered by injury or infection and is designed to return the body to homeostasis. However, uncontrolled or sustained inflammation can be deleterious and has been shown to be involved in the etiology of several diseases, including inflammatory bowel disorder and asthma. Therefore, effective anti-inflammatory signaling is important in the maintenance of homeostasis in the body. However, the inter-play between pro-and anti-inflammatory signaling is not fully understood. In the present study, we develop a mathematical model to describe integrated pro-and anti-inflammatory signaling in macrophages. The model incorporates the feedback effects of de novo synthesized pro-inflammatory (tumor necrosis factor α; TNF-α) and anti-inflammatory (interleukin-10; IL-10) cytokines on the activation of the transcription factor nuclear factor κB (NF-κB) under continuous lipopolysaccharide (LPS) stimulation (mimicking bacterial infection). In the model, IL-10 upregulates its own production (positive feedback) and also downregulates TNF-α production through NF-κB (negative feedback). In addition, TNF-α upregulates its own production through NF-κB (positive feedback). Eight model parameters are selected for estimation involving sensitivity analysis and clustering techniques. We validate the mathematical model predictions by measuring phosphorylated OPEN ACCESSProcesses 2015, 3 2 NF-κB, de novo synthesized TNF-α and IL-10 in RAW 264.7 macrophages exposed to LPS. This integrated model represents a first step towards modeling the interaction between proand anti-inflammatory signaling.

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“…Because CREB and STAT3 need to get phosphorylated for promoter binding (33, 34), we therefore, checked the phosphorylation status of both proteins after infection in RAW 264.7 cells. LPS was used as a positive control as it is a strong inducer of CREB and STAT3 activation (35)(36)(37)(38). We ruled out NF-B as a putative transcription factor for MCL-1, because previous reports documented that NF-B was not activated during L. donovani infection (39).…”

Section: D-treated Uninfected Cells) During Infectionmentioning

confidence: 99%

Leishmania donovani Exploits Myeloid Cell Leukemia 1 (MCL-1) Protein to Prevent Mitochondria-dependent Host Cell Apoptosis

Giri

Srivastav

Basu

et al. 2016

Journal of Biological Chemistry

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Apoptosis is one of the mechanisms used by host cells to remove unwanted intracellular organisms, and often found to be subverted by pathogens through use of host anti-apoptotic proteins. In the present study, with the help of in vitro and in vivo approaches, we documented that the macrophage anti-apoptotic protein myeloid cell leukemia 1 (MCL-1) is exploited by the intra-macrophage parasite Leishmania donovani to protect their "home" from actinomycin D-induced mitochondria-dependent apoptosis. Among all the anti-apoptotic BCL-2 family members, infection preferentially up-regulated expression of MCL-1 at both the mRNA and protein levels and compared with infected control, MCL-1-silenced infected macrophages documented enhanced caspase activity and increased apoptosis when subjected to actinomycin D treatment. Phosphorylation kinetics and ChIP assay demonstrated that infection-induced MCL-1 expression was regulated by transcription factor CREB (cAMP-response element-binding protein) and silencing of CREB resulted in reduced expression of MCL-1 and increased apoptosis. During infection, MCL-1 was found to be localized in mitochondria and this was significantly reduced in Tom70-silenced macrophages, suggesting the active role of TOM70 in MCL-1 transport. In the mitochondria, MCL-1 interacts with the major pro-apoptotic protein BAK and prevents BAK-BAK homo-oligomer formation thereby preventing cytochrome c release-mediated mitochondrial dysfunction. Silencing of MCL-1 in the spleen of infected mice showed decreased parasite burden and increased induction of splenocyte apoptosis. Collectively our results showed that L. donovani exploited the macrophage anti-apoptotic protein MCL-1 to prevent BAK-mediated mitochondria-dependent apoptosis thereby protecting its niche, which is essential for disease progression.Leishmania donovani, an obligate intracellular parasite, is the causative agent of the fatal visceral leishmaniasis (1). After entry into the macrophages, it survives and replicates inside the acidified phagolysosomes of macrophages (2). Its persistence to resist the host immune system determines the extent of pathogenicity and requires extensive manipulation of macrophage defense (3). One of the vital mechanisms by which host cells defend themselves against intracellular pathogens is the induction of apoptosis (4, 5). On the contrary, pathogens relentlessly try to defeat the host defense systems and evolved a number of ways to inhibit host cell apoptosis, which allows them more time to replicate (6). Various studies have documented the molecular mechanisms in virus (7), bacteria (8), and protozoan parasites (9) that tamper with the host defensive apoptotic machinery. Leishmania, being an obligate intracellular parasite, makes host cells resistant to a variety of pro-apoptotic signals in murine and human cell lines. L. donovani infection protects bone marrow-derived macrophages (BMDM) 2 from growth factor withdrawal-induced apoptosis (10). Infection with Leishmania infantum reduces actinomycin D-induced cell dea...

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Role of endogenous IL-10 in LPS-induced STAT3 activation and IL-1 receptor antagonist gene expression

Cited by 46 publications

References 37 publications

B Cells Modulate Systemic Responses to Pneumocystis murina Lung Infection and Protect On-Demand Hematopoiesis via T Cell-Independent Innate Mechanisms when Type I Interferon Signaling Is Absent

B Cells Modulate Systemic Responses to Pneumocystis murina Lung Infection and Protect On-Demand Hematopoiesis via T Cell-Independent Innate Mechanisms when Type I Interferon Signaling Is Absent

Mathematical Modeling of Pro- and Anti-Inflammatory Signaling in Macrophages

Leishmania donovani Exploits Myeloid Cell Leukemia 1 (MCL-1) Protein to Prevent Mitochondria-dependent Host Cell Apoptosis

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