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 improves the pro-angiogenic properties of MC through a Fyn kinase-dependent mechanism. Circulating IgE binds to the FcϵRI receptor on MC surface inducing the secretion of pro-angiogenic factors able to promote tumor angiogenesis and contribute to melanoma tumor growth. Fyn kinase is an important element on IgE-dependent production of pro-angiogenic factors in MC.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 8: IgE improves the pro-angiogenic properties of MC through a Fyn kinase-dependent mechanism. Circulating IgE binds to the FcϵRI receptor on MC surface inducing the secretion of pro-angiogenic factors able to promote tumor angiogenesis and contribute to melanoma tumor growth. Fyn kinase is an important element on IgE-dependent production of pro-angiogenic factors in MC.

Mentions: Our data suggest that monomeric IgE is able to potentiate the pro-tumorigenic properties of MC in a Fyn kinase-dependent fashion (Figure 8). Therefore, perturbing Fyn-activated signaling pathways to inhibit MC-dependent events leading to neovascularization of solid tumors should be evaluated in future studies.


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-angiogenic properties of MC through a Fyn kinase-dependent mechanism. Circulating IgE binds to the FcϵRI receptor on MC surface inducing the secretion of pro-angiogenic factors able to promote tumor angiogenesis and contribute to melanoma tumor growth. Fyn kinase is an important element on IgE-dependent production of pro-angiogenic factors in MC.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 8: IgE improves the pro-angiogenic properties of MC through a Fyn kinase-dependent mechanism. Circulating IgE binds to the FcϵRI receptor on MC surface inducing the secretion of pro-angiogenic factors able to promote tumor angiogenesis and contribute to melanoma tumor growth. Fyn kinase is an important element on IgE-dependent production of pro-angiogenic factors in MC.
Mentions: Our data suggest that monomeric IgE is able to potentiate the pro-tumorigenic properties of MC in a Fyn kinase-dependent fashion (Figure 8). Therefore, perturbing Fyn-activated signaling pathways to inhibit MC-dependent events leading to neovascularization of solid tumors should be evaluated in future studies.

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