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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.

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IgE improves the pro-tumorigenic properties of MC. (A and B) Participation of MC on IgE-induced melanoma tumor growth. C57BL6/J (WT), Wsh and Wsh Rec WT mice 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 four weeks after inoculation. Representative pictures of tumors from WT, Wsh and Wsh Rec WT mice after four weeks of inoculation are shown in A. Mean tumor weight of WT, Wsh and Wsh Rec WT mice. Mean ± SEM (n = 7-12). *, P < 0.05 versus IgE-treated mice; #, P < 0.05 versus WT IgE-treated mice; &, P < 0.05 versus Wsh IgE-treated mice. (C) Histological analysis of tissue biopsies. Ear pinna sections (2.5 μm) were stained with H&E and TB. Blood vessels are indicated by arrows and MC by arrowheads. Pictures are representative images (n = 2-3). Scale bar = 20 μm. (D) Quantification of blood vessels in ear pinna from treated animals. Mean ± SEM (n = 3). *, P < 0.05 versus WT-IgE + B16; α, P < 0.001 versus WT-IgE + B16; β, P < 0.001 versus WT + IgE + B16; λ, P < 0.05 versus WT-IgE + B16; δ, P < 0.001 versus Wsh-IgE + B16; ø, P < 0.001 versus Wsh Rec WT-IgE + B16; Ω, P < 0.001 versus Wsh + IgE + B16; Ψ, P < 0.01 versus WT + IgE + B16; ∑, P < 0.05 versus Wsh-IgE + B16.
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Figure 6: IgE improves the pro-tumorigenic properties of MC. (A and B) Participation of MC on IgE-induced melanoma tumor growth. C57BL6/J (WT), Wsh and Wsh Rec WT mice 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 four weeks after inoculation. Representative pictures of tumors from WT, Wsh and Wsh Rec WT mice after four weeks of inoculation are shown in A. Mean tumor weight of WT, Wsh and Wsh Rec WT mice. Mean ± SEM (n = 7-12). *, P < 0.05 versus IgE-treated mice; #, P < 0.05 versus WT IgE-treated mice; &, P < 0.05 versus Wsh IgE-treated mice. (C) Histological analysis of tissue biopsies. Ear pinna sections (2.5 μm) were stained with H&E and TB. Blood vessels are indicated by arrows and MC by arrowheads. Pictures are representative images (n = 2-3). Scale bar = 20 μm. (D) Quantification of blood vessels in ear pinna from treated animals. Mean ± SEM (n = 3). *, P < 0.05 versus WT-IgE + B16; α, P < 0.001 versus WT-IgE + B16; β, P < 0.001 versus WT + IgE + B16; λ, P < 0.05 versus WT-IgE + B16; δ, P < 0.001 versus Wsh-IgE + B16; ø, P < 0.001 versus Wsh Rec WT-IgE + B16; Ω, P < 0.001 versus Wsh + IgE + B16; Ψ, P < 0.01 versus WT + IgE + B16; ∑, P < 0.05 versus Wsh-IgE + B16.

Mentions: When B16 melanoma cells were inoculated in MC-deficient mice (Wsh), the size of the tumors after 28 days was significantly lower than the observed in WT mice (Figure 6A-B). As expected, normal tumor size was recovered after the reconstitution of Wsh animals with BMMCs derived from WT mice (Wsh Rec WT). Interestingly, monomeric IgE importantly increased the size of melanoma tumors on WT and Wsh Rec WT mice but this effect was not observed in Wsh animals treated with IgE. The effect of IgE on melanoma tumor growth positively correlated with the capacity of IgE to induce anaphylactic reactions, since Evans blue extravasation in Wsh Rec WT mice was similar to the observed in C57BL6/J mice under the same treatment (data not shown).


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 improves the pro-tumorigenic properties of MC. (A and B) Participation of MC on IgE-induced melanoma tumor growth. C57BL6/J (WT), Wsh and Wsh Rec WT mice 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 four weeks after inoculation. Representative pictures of tumors from WT, Wsh and Wsh Rec WT mice after four weeks of inoculation are shown in A. Mean tumor weight of WT, Wsh and Wsh Rec WT mice. Mean ± SEM (n = 7-12). *, P < 0.05 versus IgE-treated mice; #, P < 0.05 versus WT IgE-treated mice; &, P < 0.05 versus Wsh IgE-treated mice. (C) Histological analysis of tissue biopsies. Ear pinna sections (2.5 μm) were stained with H&E and TB. Blood vessels are indicated by arrows and MC by arrowheads. Pictures are representative images (n = 2-3). Scale bar = 20 μm. (D) Quantification of blood vessels in ear pinna from treated animals. Mean ± SEM (n = 3). *, P < 0.05 versus WT-IgE + B16; α, P < 0.001 versus WT-IgE + B16; β, P < 0.001 versus WT + IgE + B16; λ, P < 0.05 versus WT-IgE + B16; δ, P < 0.001 versus Wsh-IgE + B16; ø, P < 0.001 versus Wsh Rec WT-IgE + B16; Ω, P < 0.001 versus Wsh + IgE + B16; Ψ, P < 0.01 versus WT + IgE + B16; ∑, P < 0.05 versus Wsh-IgE + B16.
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Figure 6: IgE improves the pro-tumorigenic properties of MC. (A and B) Participation of MC on IgE-induced melanoma tumor growth. C57BL6/J (WT), Wsh and Wsh Rec WT mice 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 four weeks after inoculation. Representative pictures of tumors from WT, Wsh and Wsh Rec WT mice after four weeks of inoculation are shown in A. Mean tumor weight of WT, Wsh and Wsh Rec WT mice. Mean ± SEM (n = 7-12). *, P < 0.05 versus IgE-treated mice; #, P < 0.05 versus WT IgE-treated mice; &, P < 0.05 versus Wsh IgE-treated mice. (C) Histological analysis of tissue biopsies. Ear pinna sections (2.5 μm) were stained with H&E and TB. Blood vessels are indicated by arrows and MC by arrowheads. Pictures are representative images (n = 2-3). Scale bar = 20 μm. (D) Quantification of blood vessels in ear pinna from treated animals. Mean ± SEM (n = 3). *, P < 0.05 versus WT-IgE + B16; α, P < 0.001 versus WT-IgE + B16; β, P < 0.001 versus WT + IgE + B16; λ, P < 0.05 versus WT-IgE + B16; δ, P < 0.001 versus Wsh-IgE + B16; ø, P < 0.001 versus Wsh Rec WT-IgE + B16; Ω, P < 0.001 versus Wsh + IgE + B16; Ψ, P < 0.01 versus WT + IgE + B16; ∑, P < 0.05 versus Wsh-IgE + B16.
Mentions: When B16 melanoma cells were inoculated in MC-deficient mice (Wsh), the size of the tumors after 28 days was significantly lower than the observed in WT mice (Figure 6A-B). As expected, normal tumor size was recovered after the reconstitution of Wsh animals with BMMCs derived from WT mice (Wsh Rec WT). Interestingly, monomeric IgE importantly increased the size of melanoma tumors on WT and Wsh Rec WT mice but this effect was not observed in Wsh animals treated with IgE. The effect of IgE on melanoma tumor growth positively correlated with the capacity of IgE to induce anaphylactic reactions, since Evans blue extravasation in Wsh Rec WT mice was similar to the observed in C57BL6/J mice under the same treatment (data not shown).

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