Limits...
Immunoglobulin E induces VEGF production in mast cells and potentiates their pro-tumorigenic actions through a Fyn kinase-dependent mechanism.

Jiménez-Andrade GY, Ibarra-Sánchez A, González D, Lamas M, González-Espinosa C - J Hematol Oncol (2013)

Bottom Line: Although effects of IgE have been suggested to relay on the low-intensity activation of distinct effector elements of the immune system, such as mast cells (MC), experimental evidence on the role of IgE-induced production of inflammatory mediators on specific pathologies is scarce.In this work, we investigated the effect of monomeric IgE (in the absence of antigen) on the production of VEGF in MC, analyzed if monomeric IgE could exacerbate the pro-tumorigenic properties of that cell type and characterized some of the molecular mechanisms behind the effects of IgE on VEGF production and tumor growth.Our data suggest that monomeric IgE, in the absence of antigen, induces VEGF production in MC and in vivo contributes to melanoma tumor growth through a Fyn kinase-dependent mechanism.

View Article: PubMed Central - HTML - PubMed

Affiliation: Departamento de Farmacobiología, Cinvestav, IPN, Sede Sur, Calzada de los Tenorios 235, Col. Granjas Coapa, Tlalpan CP 14330, Mexico City, Mexico.

ABSTRACT

Background: High concentrations of plasmatic IgE have been related to distinct systemic inflammatory conditions that frequently predispose individuals to hypersensitivity reactions. Although effects of IgE have been suggested to relay on the low-intensity activation of distinct effector elements of the immune system, such as mast cells (MC), experimental evidence on the role of IgE-induced production of inflammatory mediators on specific pathologies is scarce. MC are an important component in tumor microenvironment where they seem to secrete a number of immunomodulatory and angiogenic mediators, such as the Vascular Endothelial Growth Factor (VEGF) by not well-described mechanisms. In this work, we investigated the effect of monomeric IgE (in the absence of antigen) on the production of VEGF in MC, analyzed if monomeric IgE could exacerbate the pro-tumorigenic properties of that cell type and characterized some of the molecular mechanisms behind the effects of IgE on VEGF production and tumor growth.

Methods: For in vitro studies, murine bone marrow-derived mast cells (BMMCs) were used. Pharmacological inhibitors and phosphorylation of key elements controlling VEGF secretion and protein translation were used to characterize the mechanism of VEGF production triggered by IgE.In vivo, the effect of a single i.v. administration of monomeric IgE on B16 melanoma tumor weight, intratumoral blood vessel formation and tumor-associated MC was assessed in four groups of mice: MC-proficient (WT), MC-deficient (Wsh), Wsh reconstituted with MC derived from WT mice (Wsh Rec WT) and Wsh reconstituted with MC derived from Fyn -/- mice (Wsh Rec Fyn -/-).

Results: Monomeric IgE induced VEGF secretion through a Fyn kinase-dependent mechanism and modulated de novo protein synthesis modifying the activity of the translational regulator 4E-BP1 in BMMCs. In vivo, monomeric IgE increased melanoma tumor growth, peritumoral MC and blood vessel numbers in WT but not in Wsh mice. The positive effects of IgE on melanoma tumor growth were reproduced after reconstitution of Wsh mice with WT but not with Fyn -/- BMMCs.

Conclusion: Our data suggest that monomeric IgE, in the absence of antigen, induces VEGF production in MC and in vivo contributes to melanoma tumor growth through a Fyn kinase-dependent mechanism.

Show MeSH

Related in: MedlinePlus

IgE causes increased melanoma tumor growth. (A) Effect of IgE on B16 melanoma tumor weight in C57BL/6J mice. Animals were treated with a single i.v. administration of saline (−IgE) or monoclonal anti-DNP IgE (750 ng/mouse; +IgE). Twenty four hours later, mice were s.c. inoculated with B16 melanoma cells (+B16) in one ear pinna and tumor weight was determined after four weeks of inoculation. Upper panel, a representative picture of vehicle or IgE-treated mice and vehicle or B16 cells-treated ear pinna. Lower panel, quantification of tumor weight. Results are shown as the mean ± SEM (n = 11-12). *, P < 0.05 versus + IgE mice. (B) Histological analysis of tissue biopsies. Ear pinna sections (2.5 μm) were stained with H&E (upper pictures) and TB (lower pictures). Blood vessels are indicated by arrows and MC by arrowheads. Photos are representative images from distinct mice (n = 2-4). Scale bar = 20 μm. (C) Quantification of MC by TB staining. Data are expressed as mean ± SEM from two sections per mouse, (n = 2-4). *, P < 0.05 versus –IgE + BL6. (D) quantification of blood vessels per ear pinna in tissue sections. Mean ± SEM (n = 3). *, P < 0.05 versus –IgE + BL6. (E) Effect of Bevacizumab on the IgE-dependent effects on melanoma tumor growth. Mice were treated with Bevacizumab (Beva; 10 mg/kg; s.c.) biweekly, starting 24 h after inoculation of melanoma cells. Ear pinna were removed and tumors were measured as in panel A. Data are expressed as the mean ± SEM (n = 4-11). *, P < 0.05 versus –IgE + BL6.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3750531&req=5

Figure 5: IgE causes increased melanoma tumor growth. (A) Effect of IgE on B16 melanoma tumor weight in C57BL/6J mice. Animals were treated with a single i.v. administration of saline (−IgE) or monoclonal anti-DNP IgE (750 ng/mouse; +IgE). Twenty four hours later, mice were s.c. inoculated with B16 melanoma cells (+B16) in one ear pinna and tumor weight was determined after four weeks of inoculation. Upper panel, a representative picture of vehicle or IgE-treated mice and vehicle or B16 cells-treated ear pinna. Lower panel, quantification of tumor weight. Results are shown as the mean ± SEM (n = 11-12). *, P < 0.05 versus + IgE mice. (B) Histological analysis of tissue biopsies. Ear pinna sections (2.5 μm) were stained with H&E (upper pictures) and TB (lower pictures). Blood vessels are indicated by arrows and MC by arrowheads. Photos are representative images from distinct mice (n = 2-4). Scale bar = 20 μm. (C) Quantification of MC by TB staining. Data are expressed as mean ± SEM from two sections per mouse, (n = 2-4). *, P < 0.05 versus –IgE + BL6. (D) quantification of blood vessels per ear pinna in tissue sections. Mean ± SEM (n = 3). *, P < 0.05 versus –IgE + BL6. (E) Effect of Bevacizumab on the IgE-dependent effects on melanoma tumor growth. Mice were treated with Bevacizumab (Beva; 10 mg/kg; s.c.) biweekly, starting 24 h after inoculation of melanoma cells. Ear pinna were removed and tumors were measured as in panel A. Data are expressed as the mean ± SEM (n = 4-11). *, P < 0.05 versus –IgE + BL6.

Mentions: To evaluate the effect of IgE on melanoma tumor growth, C57BL6/J (WT) mice were treated with a single i.v. administration of saline or monomeric IgE (750 ng/mouse) and twenty four hours later, mice were subcutaneously (s.c.) inoculated with B16 melanoma cells in one ear pinna and generated tumors were removed after four weeks. Tumors obtained from IgE-treated mice (+IgE) were larger than those obtained from saline-treated mice (−IgE) (Figure 5A). Histopathologic analysis of tumor sections utilizing hematoxilin-eosin (H&E) and toluidine blue (TB) stains showed that those obtained from IgE-treated mice presented significantly higher numbers of blood vessels inside the tumor and MC in the peritumoral area (Figure 5B-D). The role of VEGF on melanoma tumor growth was verified in our system by the use of the neutralizing anti-VEGF antibody Bevacizumab (Beva; Figure 5E). As expected, administration of Beva (10 mg/kg) diminished tumor size. Remarkably, the effect of IgE on tumor growth was prevented by the administration of that agent.


Immunoglobulin E induces VEGF production in mast cells and potentiates their pro-tumorigenic actions through a Fyn kinase-dependent mechanism.

Jiménez-Andrade GY, Ibarra-Sánchez A, González D, Lamas M, González-Espinosa C - J Hematol Oncol (2013)

IgE causes increased melanoma tumor growth. (A) Effect of IgE on B16 melanoma tumor weight in C57BL/6J mice. Animals were treated with a single i.v. administration of saline (−IgE) or monoclonal anti-DNP IgE (750 ng/mouse; +IgE). Twenty four hours later, mice were s.c. inoculated with B16 melanoma cells (+B16) in one ear pinna and tumor weight was determined after four weeks of inoculation. Upper panel, a representative picture of vehicle or IgE-treated mice and vehicle or B16 cells-treated ear pinna. Lower panel, quantification of tumor weight. Results are shown as the mean ± SEM (n = 11-12). *, P < 0.05 versus + IgE mice. (B) Histological analysis of tissue biopsies. Ear pinna sections (2.5 μm) were stained with H&E (upper pictures) and TB (lower pictures). Blood vessels are indicated by arrows and MC by arrowheads. Photos are representative images from distinct mice (n = 2-4). Scale bar = 20 μm. (C) Quantification of MC by TB staining. Data are expressed as mean ± SEM from two sections per mouse, (n = 2-4). *, P < 0.05 versus –IgE + BL6. (D) quantification of blood vessels per ear pinna in tissue sections. Mean ± SEM (n = 3). *, P < 0.05 versus –IgE + BL6. (E) Effect of Bevacizumab on the IgE-dependent effects on melanoma tumor growth. Mice were treated with Bevacizumab (Beva; 10 mg/kg; s.c.) biweekly, starting 24 h after inoculation of melanoma cells. Ear pinna were removed and tumors were measured as in panel A. Data are expressed as the mean ± SEM (n = 4-11). *, P < 0.05 versus –IgE + BL6.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3750531&req=5

Figure 5: IgE causes increased melanoma tumor growth. (A) Effect of IgE on B16 melanoma tumor weight in C57BL/6J mice. Animals were treated with a single i.v. administration of saline (−IgE) or monoclonal anti-DNP IgE (750 ng/mouse; +IgE). Twenty four hours later, mice were s.c. inoculated with B16 melanoma cells (+B16) in one ear pinna and tumor weight was determined after four weeks of inoculation. Upper panel, a representative picture of vehicle or IgE-treated mice and vehicle or B16 cells-treated ear pinna. Lower panel, quantification of tumor weight. Results are shown as the mean ± SEM (n = 11-12). *, P < 0.05 versus + IgE mice. (B) Histological analysis of tissue biopsies. Ear pinna sections (2.5 μm) were stained with H&E (upper pictures) and TB (lower pictures). Blood vessels are indicated by arrows and MC by arrowheads. Photos are representative images from distinct mice (n = 2-4). Scale bar = 20 μm. (C) Quantification of MC by TB staining. Data are expressed as mean ± SEM from two sections per mouse, (n = 2-4). *, P < 0.05 versus –IgE + BL6. (D) quantification of blood vessels per ear pinna in tissue sections. Mean ± SEM (n = 3). *, P < 0.05 versus –IgE + BL6. (E) Effect of Bevacizumab on the IgE-dependent effects on melanoma tumor growth. Mice were treated with Bevacizumab (Beva; 10 mg/kg; s.c.) biweekly, starting 24 h after inoculation of melanoma cells. Ear pinna were removed and tumors were measured as in panel A. Data are expressed as the mean ± SEM (n = 4-11). *, P < 0.05 versus –IgE + BL6.
Mentions: To evaluate the effect of IgE on melanoma tumor growth, C57BL6/J (WT) mice were treated with a single i.v. administration of saline or monomeric IgE (750 ng/mouse) and twenty four hours later, mice were subcutaneously (s.c.) inoculated with B16 melanoma cells in one ear pinna and generated tumors were removed after four weeks. Tumors obtained from IgE-treated mice (+IgE) were larger than those obtained from saline-treated mice (−IgE) (Figure 5A). Histopathologic analysis of tumor sections utilizing hematoxilin-eosin (H&E) and toluidine blue (TB) stains showed that those obtained from IgE-treated mice presented significantly higher numbers of blood vessels inside the tumor and MC in the peritumoral area (Figure 5B-D). The role of VEGF on melanoma tumor growth was verified in our system by the use of the neutralizing anti-VEGF antibody Bevacizumab (Beva; Figure 5E). As expected, administration of Beva (10 mg/kg) diminished tumor size. Remarkably, the effect of IgE on tumor growth was prevented by the administration of that agent.

Bottom Line: Although effects of IgE have been suggested to relay on the low-intensity activation of distinct effector elements of the immune system, such as mast cells (MC), experimental evidence on the role of IgE-induced production of inflammatory mediators on specific pathologies is scarce.In this work, we investigated the effect of monomeric IgE (in the absence of antigen) on the production of VEGF in MC, analyzed if monomeric IgE could exacerbate the pro-tumorigenic properties of that cell type and characterized some of the molecular mechanisms behind the effects of IgE on VEGF production and tumor growth.Our data suggest that monomeric IgE, in the absence of antigen, induces VEGF production in MC and in vivo contributes to melanoma tumor growth through a Fyn kinase-dependent mechanism.

View Article: PubMed Central - HTML - PubMed

Affiliation: Departamento de Farmacobiología, Cinvestav, IPN, Sede Sur, Calzada de los Tenorios 235, Col. Granjas Coapa, Tlalpan CP 14330, Mexico City, Mexico.

ABSTRACT

Background: High concentrations of plasmatic IgE have been related to distinct systemic inflammatory conditions that frequently predispose individuals to hypersensitivity reactions. Although effects of IgE have been suggested to relay on the low-intensity activation of distinct effector elements of the immune system, such as mast cells (MC), experimental evidence on the role of IgE-induced production of inflammatory mediators on specific pathologies is scarce. MC are an important component in tumor microenvironment where they seem to secrete a number of immunomodulatory and angiogenic mediators, such as the Vascular Endothelial Growth Factor (VEGF) by not well-described mechanisms. In this work, we investigated the effect of monomeric IgE (in the absence of antigen) on the production of VEGF in MC, analyzed if monomeric IgE could exacerbate the pro-tumorigenic properties of that cell type and characterized some of the molecular mechanisms behind the effects of IgE on VEGF production and tumor growth.

Methods: For in vitro studies, murine bone marrow-derived mast cells (BMMCs) were used. Pharmacological inhibitors and phosphorylation of key elements controlling VEGF secretion and protein translation were used to characterize the mechanism of VEGF production triggered by IgE.In vivo, the effect of a single i.v. administration of monomeric IgE on B16 melanoma tumor weight, intratumoral blood vessel formation and tumor-associated MC was assessed in four groups of mice: MC-proficient (WT), MC-deficient (Wsh), Wsh reconstituted with MC derived from WT mice (Wsh Rec WT) and Wsh reconstituted with MC derived from Fyn -/- mice (Wsh Rec Fyn -/-).

Results: Monomeric IgE induced VEGF secretion through a Fyn kinase-dependent mechanism and modulated de novo protein synthesis modifying the activity of the translational regulator 4E-BP1 in BMMCs. In vivo, monomeric IgE increased melanoma tumor growth, peritumoral MC and blood vessel numbers in WT but not in Wsh mice. The positive effects of IgE on melanoma tumor growth were reproduced after reconstitution of Wsh mice with WT but not with Fyn -/- BMMCs.

Conclusion: Our data suggest that monomeric IgE, in the absence of antigen, induces VEGF production in MC and in vivo contributes to melanoma tumor growth through a Fyn kinase-dependent mechanism.

Show MeSH
Related in: MedlinePlus