Murine IL-4 is able to signal via chimeric human IL-4Ralpha/mouse gamma-chain receptor

Elmarie Myburgh; William G C Horsnell; Antony J Cutler; Berenice Arendse; Masato Kubo; Frank Brombacher

doi:10.1016/j.molimm.2007.09.009

Murine IL-4 is able to signal via chimeric human IL-4Ralpha/mouse gamma-chain receptor

Elmarie Myburgh, William G C Horsnell, Antony J Cutler, Berenice Arendse, Masato Kubo, Frank Brombacher

The Hull York Medical School

Research output: Contribution to journal › Article › peer-review

Abstract

Human IL-4Ralpha binds to mouse gammac resulting in a chimeric receptor specific for human IL-4 but not mouse IL-4, providing in principle an inducible hIL-4 system. We investigated the in vitro and in vivo characteristics of human IL-4Ralpha transgenic mice on a mouse IL-4Ralpha-deficient background (hIL-4Ralpha Tg/mIL-4Ralpha(-/-)). The integrity of lymphocyte-specific hIL-4Ralpha expression in hIL-4Ralpha Tg/mIL-4Ralpha(-/-) mice was demonstrated by FACS analysis. This was confirmed in functional studies as lymphocytes responded to recombinant hIL-4 but not mIL-4 or mIL-13 in proliferation and T helper differentiation assays, demonstrating species-specificity and inducibility of the chimeric receptor in vitro. We then infected transgenic mice with Nippostrongylus brasiliensis, known to induce a strong Type 2 response in wild-type mice. As expected hIL-4Ralpha Tg/mIL-4Ralpha(-/-) mice were unable to expel N. brasiliensis worms which confirms unresponsiveness in non-lymphocytes. However they developed a Th2 cytokine and IgE response in the absence of induction with hIL-4. These results suggested that lymphocyte-specific IL-4Ralpha responsiveness was still present in vivo. Neutralization of endogenous mIL-4 resulted in inhibition of N. brasiliensis-induced Th2 cytokine and total IgE production in hIL-4Ralpha Tg/mIL-4Ralpha(-/-) mice suggesting that mIL-4 was involved. Intercrossing hIL-4Ralpha Tg/mIL-4Ralpha(-/-) mice with mIL-4(-/-)/mIL-13(-/-) mice completely abrogated Type 2 responses in N. brasiliensis infections. Together, these data demonstrate that mIL-4 triggered the hIL-4Ralpha/mgammac chimeric receptor in vivo.

Original language	English
Pages (from-to)	1327-36
Number of pages	10
Journal	Molecular immunology
Volume	45
Issue number	5
DOIs	https://doi.org/10.1016/j.molimm.2007.09.009
Publication status	Published - Mar 2008

Keywords

Animals
CD4-Positive T-Lymphocytes/immunology
Humans
Interleukin Receptor Common gamma Subunit/immunology
Interleukin-4/metabolism
Interleukin-4 Receptor alpha Subunit/genetics
Mice
Mice, Transgenic
Nippostrongylus/immunology
Recombinant Fusion Proteins
Signal Transduction/immunology

Access to Document

10.1016/j.molimm.2007.09.009

Cite this

@article{4e02483f9fe24b4c9829bdf93adc6e0c,

title = "Murine IL-4 is able to signal via chimeric human IL-4Ralpha/mouse gamma-chain receptor",

abstract = "Human IL-4Ralpha binds to mouse gammac resulting in a chimeric receptor specific for human IL-4 but not mouse IL-4, providing in principle an inducible hIL-4 system. We investigated the in vitro and in vivo characteristics of human IL-4Ralpha transgenic mice on a mouse IL-4Ralpha-deficient background (hIL-4Ralpha Tg/mIL-4Ralpha(-/-)). The integrity of lymphocyte-specific hIL-4Ralpha expression in hIL-4Ralpha Tg/mIL-4Ralpha(-/-) mice was demonstrated by FACS analysis. This was confirmed in functional studies as lymphocytes responded to recombinant hIL-4 but not mIL-4 or mIL-13 in proliferation and T helper differentiation assays, demonstrating species-specificity and inducibility of the chimeric receptor in vitro. We then infected transgenic mice with Nippostrongylus brasiliensis, known to induce a strong Type 2 response in wild-type mice. As expected hIL-4Ralpha Tg/mIL-4Ralpha(-/-) mice were unable to expel N. brasiliensis worms which confirms unresponsiveness in non-lymphocytes. However they developed a Th2 cytokine and IgE response in the absence of induction with hIL-4. These results suggested that lymphocyte-specific IL-4Ralpha responsiveness was still present in vivo. Neutralization of endogenous mIL-4 resulted in inhibition of N. brasiliensis-induced Th2 cytokine and total IgE production in hIL-4Ralpha Tg/mIL-4Ralpha(-/-) mice suggesting that mIL-4 was involved. Intercrossing hIL-4Ralpha Tg/mIL-4Ralpha(-/-) mice with mIL-4(-/-)/mIL-13(-/-) mice completely abrogated Type 2 responses in N. brasiliensis infections. Together, these data demonstrate that mIL-4 triggered the hIL-4Ralpha/mgammac chimeric receptor in vivo.",

keywords = "Animals, CD4-Positive T-Lymphocytes/immunology, Humans, Interleukin Receptor Common gamma Subunit/immunology, Interleukin-4/metabolism, Interleukin-4 Receptor alpha Subunit/genetics, Mice, Mice, Transgenic, Nippostrongylus/immunology, Recombinant Fusion Proteins, Signal Transduction/immunology",

author = "Elmarie Myburgh and Horsnell, {William G C} and Cutler, {Antony J} and Berenice Arendse and Masato Kubo and Frank Brombacher",

year = "2008",

month = mar,

doi = "10.1016/j.molimm.2007.09.009",

language = "English",

volume = "45",

pages = "1327--36",

journal = "Molecular immunology",

issn = "0161-5890",

publisher = "Elsevier",

number = "5",

}

TY - JOUR

T1 - Murine IL-4 is able to signal via chimeric human IL-4Ralpha/mouse gamma-chain receptor

AU - Myburgh, Elmarie

AU - Horsnell, William G C

AU - Cutler, Antony J

AU - Arendse, Berenice

AU - Kubo, Masato

AU - Brombacher, Frank

PY - 2008/3

Y1 - 2008/3

N2 - Human IL-4Ralpha binds to mouse gammac resulting in a chimeric receptor specific for human IL-4 but not mouse IL-4, providing in principle an inducible hIL-4 system. We investigated the in vitro and in vivo characteristics of human IL-4Ralpha transgenic mice on a mouse IL-4Ralpha-deficient background (hIL-4Ralpha Tg/mIL-4Ralpha(-/-)). The integrity of lymphocyte-specific hIL-4Ralpha expression in hIL-4Ralpha Tg/mIL-4Ralpha(-/-) mice was demonstrated by FACS analysis. This was confirmed in functional studies as lymphocytes responded to recombinant hIL-4 but not mIL-4 or mIL-13 in proliferation and T helper differentiation assays, demonstrating species-specificity and inducibility of the chimeric receptor in vitro. We then infected transgenic mice with Nippostrongylus brasiliensis, known to induce a strong Type 2 response in wild-type mice. As expected hIL-4Ralpha Tg/mIL-4Ralpha(-/-) mice were unable to expel N. brasiliensis worms which confirms unresponsiveness in non-lymphocytes. However they developed a Th2 cytokine and IgE response in the absence of induction with hIL-4. These results suggested that lymphocyte-specific IL-4Ralpha responsiveness was still present in vivo. Neutralization of endogenous mIL-4 resulted in inhibition of N. brasiliensis-induced Th2 cytokine and total IgE production in hIL-4Ralpha Tg/mIL-4Ralpha(-/-) mice suggesting that mIL-4 was involved. Intercrossing hIL-4Ralpha Tg/mIL-4Ralpha(-/-) mice with mIL-4(-/-)/mIL-13(-/-) mice completely abrogated Type 2 responses in N. brasiliensis infections. Together, these data demonstrate that mIL-4 triggered the hIL-4Ralpha/mgammac chimeric receptor in vivo.

AB - Human IL-4Ralpha binds to mouse gammac resulting in a chimeric receptor specific for human IL-4 but not mouse IL-4, providing in principle an inducible hIL-4 system. We investigated the in vitro and in vivo characteristics of human IL-4Ralpha transgenic mice on a mouse IL-4Ralpha-deficient background (hIL-4Ralpha Tg/mIL-4Ralpha(-/-)). The integrity of lymphocyte-specific hIL-4Ralpha expression in hIL-4Ralpha Tg/mIL-4Ralpha(-/-) mice was demonstrated by FACS analysis. This was confirmed in functional studies as lymphocytes responded to recombinant hIL-4 but not mIL-4 or mIL-13 in proliferation and T helper differentiation assays, demonstrating species-specificity and inducibility of the chimeric receptor in vitro. We then infected transgenic mice with Nippostrongylus brasiliensis, known to induce a strong Type 2 response in wild-type mice. As expected hIL-4Ralpha Tg/mIL-4Ralpha(-/-) mice were unable to expel N. brasiliensis worms which confirms unresponsiveness in non-lymphocytes. However they developed a Th2 cytokine and IgE response in the absence of induction with hIL-4. These results suggested that lymphocyte-specific IL-4Ralpha responsiveness was still present in vivo. Neutralization of endogenous mIL-4 resulted in inhibition of N. brasiliensis-induced Th2 cytokine and total IgE production in hIL-4Ralpha Tg/mIL-4Ralpha(-/-) mice suggesting that mIL-4 was involved. Intercrossing hIL-4Ralpha Tg/mIL-4Ralpha(-/-) mice with mIL-4(-/-)/mIL-13(-/-) mice completely abrogated Type 2 responses in N. brasiliensis infections. Together, these data demonstrate that mIL-4 triggered the hIL-4Ralpha/mgammac chimeric receptor in vivo.

KW - Animals

KW - CD4-Positive T-Lymphocytes/immunology

KW - Humans

KW - Interleukin Receptor Common gamma Subunit/immunology

KW - Interleukin-4/metabolism

KW - Interleukin-4 Receptor alpha Subunit/genetics

KW - Mice

KW - Mice, Transgenic

KW - Nippostrongylus/immunology

KW - Recombinant Fusion Proteins

KW - Signal Transduction/immunology

U2 - 10.1016/j.molimm.2007.09.009

DO - 10.1016/j.molimm.2007.09.009

M3 - Article

C2 - 18029018

SN - 0161-5890

VL - 45

SP - 1327

EP - 1336

JO - Molecular immunology

JF - Molecular immunology

IS - 5

ER -