All Trans Retinoic Acid, Transforming Growth Factor β and Prostaglandin E2 in Mouse Plasma Synergize with Basophil-Secreted Interleukin-4 to M2 Polarize Murine Macrophages

Ho, Victor W.; Hofs, Elyse; Elisia, Ingrid; Lam, Vivian; Hsu, Brian; Lai, June; Luk, Beryl; Samudio, Ismael; Krystal, Gerald

doi:10.1371/journal.pone.0168072

Cited by 18 publications

(12 citation statements)

References 49 publications

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“…Our study demonstrated for the first time that IL-4 is not only an activator of the STAT6 signaling pathway but also a downstream effector in the TME that acts as a positive feedback factor. IL-4 promotes polarization into the M2-Mϕ phenotype and promotes tumor progression (47). We observed that tumor cells secrete lower levels of IL-4 after being cocultured with STAT6 −/− CD11b + cells, indicating that the pathway regulating IL-4 secretion pathway is inhibited by STAT6 deficiency in CD11b + cells but not tumor cells.…”

Section: Discussionmentioning

confidence: 99%

Activation of the IL-4/STAT6 Signaling Pathway Promotes Lung Cancer Progression by Increasing M2 Myeloid Cells

Jiang

Hao

et al. 2019

Front. Immunol.

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Emerging evidence shows that signal transducer and activator of transcription 6 (STAT6) plays critical roles in tumor development. We previously found high-level expression of STAT6 in human lung adenocarcinoma and squamous cell carcinoma, specifically in infiltrated immune cells located in the lung interstitium. Nevertheless, the role of STAT6 signaling in lung carcinogenesis and lung cancer proliferation and its underlying mechanisms remain unclear. This study aimed to investigate the role of STAT6 and the interaction between STAT6 and the tumor microenvironment in pulmonary tumorigenesis. We established a murine model of primary lung carcinogenesis in STAT6-deficient (STAT6−/−) and STAT6 wild-type (WT) BALB/c mice using the carcinogen urethane. Two-month-old male mice were intraperitoneally injected with urethane (1 g/kg) dissolved in phosphate buffered saline (PBS). Primary tumors were monitored in vivo by positron emission tomography scanning. At 4, 6, and 9 months after urethane injection, lung tumors were harvested from the STAT6−/− and WT mice for analysis. Small interfering RNA was used to downregulate the expression of STAT6 in tumor cells. Fluorescence activated cell sorting analysis was used to analyze fluorescence-conjugated cell markers. Transwell assays were used in coculturing experiments. STAT6 protein expression was detected by Western blotting, immunohistochemistry, and immunofluorescence. STAT6 mRNA expression was detected by quantitative real time-polymerase chain reaction. Cell Counting Kit-8 and colony formation assays were performed to evaluate cell proliferation. We detected high expression of STAT6 in CD11b+ cells of lung carcinoma. Our results indicate that STAT6 deficiency inhibits carcinogen-induced tumor growth and improves prognosis. STAT6 deficiency also decreased the mobilization and differentiation of CD11b+ cells. STAT6 deficiency in CD11b+ cells but not tumor cells decreased interleukin (IL)-4 secretion and the differentiation of CD11b+ cells into M2 macrophage cells. In conclusion, our findings indicate that IL-4/STAT6 signaling in CD11b+ cells promotes lung cancer progression by triggering an IL-4 positive feedback loop and increasing M2 myeloid cells. STAT6 may be a new therapeutic target for the prevention and treatment of lung cancer.

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Section: Discussionmentioning

confidence: 99%

Activation of the IL-4/STAT6 Signaling Pathway Promotes Lung Cancer Progression by Increasing M2 Myeloid Cells

Jiang

Hao

et al. 2019

Front. Immunol.

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“…atRA also inhibits the LPS-induced production of the proinflammatory cytokines TNF- α and IL-12 and potentiates IL-10 production in the THP-1 monocyte/macrophage cell line and human cord blood mononuclear cells (CBMCs) [ 63 ]. Plasma factors, such as transforming growth factor- (TGF-) β and PGE2, in combination with RA, act synergistically with IL-4 synthesized by basophils to increase the sensitivity of macrophages to IL-4, which contributes to M2 macrophage polarization and the regulation of the inflammatory process in mice [ 64 ].…”

Section: Effects Of Ra On Immune Cellsmentioning

confidence: 99%

Impact of Retinoic Acid on Immune Cells and Inflammatory Diseases

Oliveira

Teixeira

Sato

2018

Mediators of Inflammation

172

128

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Vitamin A metabolite retinoic acid (RA) plays important roles in cell growth, differentiation, organogenesis, and reproduction and a key role in mucosal immune responses. RA promotes dendritic cells to express CD103 and to produce RA, enhances the differentiation of Foxp3+ inducible regulatory T cells, and induces gut-homing specificity in T cells. Although vitamin A is crucial for maintaining homeostasis at the intestinal barrier and equilibrating immunity and tolerance, including gut dysbiosis, retinoids perform a wide variety of functions in many settings, such as the central nervous system, skin aging, allergic airway diseases, cancer prevention and therapy, and metabolic diseases. The mechanism of RA is interesting to explore as both a mucosal adjuvant and a combination therapy with other effective agents. Here, we review the effect of RA on innate and adaptive immunity with a special emphasis on inflammatory status.

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“…SHIP also blocks IL‐3 induced M2‐like Mϕ skewing, which can now been attributed to enhanced IL‐4 production by IL‐3‐treated SHIP −/− basophils . Hyperresponsive SHIP −/− basophils are the source of IL‐4 driving M(IL‐4) activation in vivo in the SHIP −/− mouse …”

Section: Macrophagesmentioning

confidence: 96%

SHIP negatively regulates type II immune responses in mast cells and macrophages

Dobranowski

Sly

2018

Journal of Leukocyte Biology

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SHIP is a hematopoietic-specific lipid phosphatase that dephosphorylates PI3K-generated PI(3,4,5)-trisphosphate. SHIP removes this second messenger from the cell membrane blunting PI3K activity in immune cells. Thus, SHIP negatively regulates mast cell activation downstream of multiple receptors. SHIP has been referred to as the "gatekeeper" of mast cell degranulation as loss of SHIP dramatically increases degranulation or permits degranulation in response to normally inert stimuli. SHIP also negatively regulates Mϕ activation, including both pro-inflammatory cytokine production downstream of pattern recognition receptors, and alternative Mϕ activation by the type II cytokines, IL-4, and IL-13. In the SHIP-deficient (SHIP ) mouse, increased mast cell and Mϕ activation leads to spontaneous inflammatory pathology at mucosal sites, which is characterized by high levels of type II inflammatory cytokines. SHIP mast cells and Mϕs have both been implicated in driving inflammation in the SHIP mouse lung. SHIP Mϕs drive Crohn's disease-like intestinal inflammation and fibrosis, which is dependent on heightened responses to innate immune stimuli generating IL-1, and IL-4 inducing abundant arginase I. Both lung and gut pathology translate to human disease as low SHIP levels and activity have been associated with allergy and with Crohn's disease in people. In this review, we summarize seminal literature and recent advances that provide insight into SHIP's role in mast cells and Mϕs, the contribution of these cell types to pathology in the SHIP mouse, and describe how these findings translate to human disease and potential therapies.

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All Trans Retinoic Acid, Transforming Growth Factor β and Prostaglandin E2 in Mouse Plasma Synergize with Basophil-Secreted Interleukin-4 to M2 Polarize Murine Macrophages

Cited by 18 publications

References 49 publications

Activation of the IL-4/STAT6 Signaling Pathway Promotes Lung Cancer Progression by Increasing M2 Myeloid Cells

Activation of the IL-4/STAT6 Signaling Pathway Promotes Lung Cancer Progression by Increasing M2 Myeloid Cells

Impact of Retinoic Acid on Immune Cells and Inflammatory Diseases

SHIP negatively regulates type II immune responses in mast cells and macrophages

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