Cytokine Response Is Determined by Duration of Receptor and Signal Transducers and Activators of Transcription 3 (STAT3) Activation

Braun, David A.; Fribourg, Miguel; Sealfon, Stuart C.

doi:10.1074/jbc.m112.386573

Cited by 142 publications

(138 citation statements)

References 32 publications

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“…Future work will be performed to identify the relationship between these factors and their contributions to signaling pathways in the granuloma and to add them to our computational model. We employed simplified versions of recently published models for STAT1, STAT3, and NF-B pathways (88,90,94). We use two representative intracellular species for each signaling pathway: a phosphorylated nuclear species (denoted with N) and a response species (denoted with R) (Fig.…”

Section: Models Of Stat1 Stat3 and Nf-b Dynamicsmentioning

confidence: 99%

Macrophage Polarization Drives Granuloma Outcome during Mycobacterium tuberculosis Infection

et al. 2015

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c Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), induces formation of granulomas, structures in which immune cells and bacteria colocalize. Macrophages are among the most abundant cell types in granulomas and have been shown to serve as both critical bactericidal cells and targets for M. tuberculosis infection and proliferation throughout the course of infection. Very little is known about how these processes are regulated, what controls macrophage microenvironment-specific polarization and plasticity, or why some granulomas control bacteria and others permit bacterial dissemination. We take a computational-biology approach to investigate mechanisms that drive macrophage polarization, function, and bacterial control in granulomas. We define a "macrophage polarization ratio" as a metric to understand how cytokine signaling translates into polarization of single macrophages in a granuloma, which in turn modulates cellular functions, including antimicrobial activity and cytokine production. Ultimately, we extend this macrophage ratio to the tissue scale and define a "granuloma polarization ratio" describing mean polarization measures for entire granulomas. Here we coupled experimental data from nonhuman primate TB granulomas to our computational model, and we predict two novel and testable hypotheses regarding macrophage profiles in TB outcomes. First, the temporal dynamics of granuloma polarization ratios are predictive of granuloma outcome. Second, stable necrotic granulomas with low CFU counts and limited inflammation are characterized by short NF-B signal activation intervals. These results suggest that the dynamics of NF-B signaling is a viable therapeutic target to promote M 1 polarization early during infection and to improve outcome.

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Section: Models Of Stat1 Stat3 and Nf-b Dynamicsmentioning

confidence: 99%

Macrophage Polarization Drives Granuloma Outcome during Mycobacterium tuberculosis Infection

et al. 2015

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“…[34][35][36] STAT3 is mainly expressed in macrophages and dendritic cells and can exhibit-depending on the stimulating cytokine-both pro-and antiinflammatory properties. 37 However, STAT3 is also found to be expressed in ALK þ anaplastic large cell lymphoma. 38 In contrast, pediatric cases of ALK À anaplastic large cell lymphoma were negative for phosphorylated STAT3.…”

Section: Discussionmentioning

confidence: 99%

A novel immunohistochemical classifier to distinguish Hodgkin lymphoma from ALK anaplastic large cell lymphoma

et al. 2014

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Classical Hodgkin lymphoma and ALK À anaplastic large cell lymphoma share many features like strong CD30 expression and usually loss of B-and T-cell markers. However, their clinical course is dramatically different with curability rates of 490% for classical Hodgkin lymphoma and an unfavorable prognosis for anaplastic large cell lymphoma. Classical Hodgkin lymphoma and ALK À anaplastic large cell lymphoma can usually be distinguished by PAX5 expression in the Hodgkin and Reed-Sternberg cells of classical Hodgkin lymphoma and expression of cytotoxic molecules in tumor cells of anaplastic large cell lymphoma. However, in some cases the differential diagnosis is difficult owing to absence of established markers. To be able to better classify these cases, we reevaluated gene expression data of microdissected tumor cells of both lymphomas for differentially expressed genes. A classifier was established, comprising four genes strongly expressed in Hodgkin and Reed-Sternberg cells of classical Hodgkin lymphoma (MDC/CCL22, CD83, STAT3, and TUBB2B). Applying this classifier to a test cohort, Hodgkin lymphoma was successfully distinguished from ALK À anaplastic large cell lymphoma with an accuracy of 97% (43/44). MDC/CCL22, CD83, and STAT3 have also been found to be expressed in antigen-presenting cells. Therefore, based on our established classifier, Hodgkin and Reed-Sternberg cells differ from tumor cells of anaplastic large cell lymphoma, which can successfully be applied for practical purposes in histopathologic diagnostics.

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“…Activation of STAT3 signaling has been implicated in the regulation of cell proliferation, differentiation, transformation, and apoptosis (Yang et al, 2007;Braun et al, 2013). Recently, the role of this pathway in lipopolysaccharide (LPS)-induced TNF-a and IL-10 production has been investigated in cultured murine AMs (MH-S cells; Meng et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

“…STAT3 is a member of the cytoplasmic protein family, and is activated by a large number of extracellular stimuli, including IL-6, IL-10, various other cytokines, granulocytecolony stimulating factor, and epidermal growth factor (Stepkowski et al, 2008;Braun et al, 2013;Hutchins et al, 2013). Activation of STAT3 signaling has been implicated in the regulation of cell proliferation, differentiation, transformation, and apoptosis (Yang et al, 2007;Braun et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

Role of IL-10 and TNF-α during Mycobacterium tuberculosis infection in murine alveolar macrophages

2016

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ABSTRACT. Mycobacterium tuberculosis (Mtb) is known to be responsible for tuberculosis (TB), but the pathogenesis of this disease and the host defense mechanisms involved are, for the most part, poorly understood. In this study, we divided 30 male C57BL/6 mice into control and infection groups, and following injection with physiological saline or Mtb, respectively, euthanized five mice from each group on days 1, 3, and 7. TNF-a and IL-10 levels were measured by enzyme-linked immunosorbent assay and flow cytometry, with the latter also being performed to assess apoptosis rates. Protein expression of STAT3 and its phosphorylated form (p-STAT3) was analyzed by western blotting. After Mtb infection, TNF-a and IL-10 levels, alveolar macrophage apoptosis, and STAT3 and p-STAT3 expression increased significantly on days 1, 3, and 7 (P < 0.05), with maximum values on day 3. Furthermore, the Pearson correlation test showed that production of the cytokines TNF-a and IL-10 correlated strongly with expression of STAT3 and p-STAT3 proteins (P < 0.05). Taken together, our results suggest that the STAT3 signaling pathway might play a key role in the regulation of cell proliferation and alveolar macrophage apoptosis in response to Mtb. This provides a theoretical mechanism behind TB pathogenesis and host defense against Mtb, and contributes towards development of an effective treatment.

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Cytokine Response Is Determined by Duration of Receptor and Signal Transducers and Activators of Transcription 3 (STAT3) Activation

Cited by 142 publications

References 32 publications

Macrophage Polarization Drives Granuloma Outcome during Mycobacterium tuberculosis Infection

Macrophage Polarization Drives Granuloma Outcome during Mycobacterium tuberculosis Infection

A novel immunohistochemical classifier to distinguish Hodgkin lymphoma from ALK anaplastic large cell lymphoma

Role of IL-10 and TNF-α during Mycobacterium tuberculosis infection in murine alveolar macrophages

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