Induced somatic inactivation of STAT3 in mice triggers the development of a fulminant form of enterocolitis

Tonino Alonzi; Ian P. Newton; Paul J. Bryce; Emma Di Carlo; Giuseppe Lattanzio; Marco Tripodi; Piero Musiani; Valeria Poli

doi:10.1016/j.cyto.2003.12.002

Induced somatic inactivation of STAT3 in mice triggers the development of a fulminant form of enterocolitis

Tonino Alonzi^*, Ian P. Newton, Paul J. Bryce, Emma Di Carlo, Giuseppe Lattanzio, Marco Tripodi, Piero Musiani, Valeria Poli

^*Corresponding author for this work

Medicine, Allergy Division

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

86 Scopus citations

Abstract

We have generated mice in which the gene encoding the transcription factor STAT3 can be inactivated in multiple cell types by triggering the endogenous production of type I interferon. Gene inactivation is particularly effective in the liver and the adipose tissue, as well as in macrophages and gut epithelial cells. Upon induction of the mutation, mice develop a wasting syndrome culminating in an aggressive and fatal form of enterocolitis, limited to the large intestine, within 2-3 weeks after the treatment. The disease is characterised by massive infiltration of the gut mucosa by macrophages, granulocytes and CD4+ cells, increased expression of endothelial adhesion molecules and high production of the cytokines interleukin (IL)-6, IL-12, interferon-γ and IL-10. IL-12 p40 plays a pivotal role in disease development as in vivo treatment with neutralising antibodies completely prevents its onset. Interestingly, oral treatment with wide spectrum antibiotics does not have any effect on either the onset or the development of colitis. Taken together, these data show that STAT3 plays a crucial role in the maintenance of intestinal homeostasis and possibly in mediating specialised cell functions in the intestinal epithelium.

Original language	English (US)
Pages (from-to)	45-56
Number of pages	12
Journal	Cytokine
Volume	26
Issue number	2
DOIs	https://doi.org/10.1016/j.cyto.2003.12.002
State	Published - Apr 21 2004

Funding

We would like to thank Drs. P. Garside and F. Powrie for critically reading the manuscript. We are grateful to Mr. D. Lunny for help with keratin immunostaining, Drs. U. Betz and K. Rajewsky for providing the MX-Cre mouse transgenic line, Drs. F. Powrie, S. Cobbold, R.L.Coffman, S. Landolfo, and A. Vecchi for the gift of antibodies, Drs. P. Crocker and R. Porter for helpful advice and Mrs. L. Malone and V. Murray-Tait for expert mouse care. STAT3-targeted mice were generated at the Istituto di Biologia Molecolare I.R.B.M. P. Angeletti by V.P. and T.A. V.P. was supported by the Wellcome Trust, MIUR (Ministero dell'Istruzione, dell'Università e della Ricerca) and AIRC (Associazione Italiana Ricerca sul Cancro). T.A. was supported by Ministero della Sanità (Ricerca Finalizzata), and was the recipient of an EC Marie Curie. E. Di C. was the recipient of a FIRC (Italian Foundation for Cancer Research) Post-doctoral fellowship.

Keywords

Conditional gene inactivation
Enterocolitis
Inflammation
Inflammatory bowel disease
STAT3

ASJC Scopus subject areas

Molecular Biology
Hematology
Biochemistry
Immunology and Allergy
Immunology

Access to Document

10.1016/j.cyto.2003.12.002

Cite this

@article{13563b839dad421e9f954b39fbd30594,

title = "Induced somatic inactivation of STAT3 in mice triggers the development of a fulminant form of enterocolitis",

abstract = "We have generated mice in which the gene encoding the transcription factor STAT3 can be inactivated in multiple cell types by triggering the endogenous production of type I interferon. Gene inactivation is particularly effective in the liver and the adipose tissue, as well as in macrophages and gut epithelial cells. Upon induction of the mutation, mice develop a wasting syndrome culminating in an aggressive and fatal form of enterocolitis, limited to the large intestine, within 2-3 weeks after the treatment. The disease is characterised by massive infiltration of the gut mucosa by macrophages, granulocytes and CD4+ cells, increased expression of endothelial adhesion molecules and high production of the cytokines interleukin (IL)-6, IL-12, interferon-γ and IL-10. IL-12 p40 plays a pivotal role in disease development as in vivo treatment with neutralising antibodies completely prevents its onset. Interestingly, oral treatment with wide spectrum antibiotics does not have any effect on either the onset or the development of colitis. Taken together, these data show that STAT3 plays a crucial role in the maintenance of intestinal homeostasis and possibly in mediating specialised cell functions in the intestinal epithelium.",

keywords = "Conditional gene inactivation, Enterocolitis, Inflammation, Inflammatory bowel disease, STAT3",

author = "Tonino Alonzi and Newton, {Ian P.} and Bryce, {Paul J.} and {Di Carlo}, Emma and Giuseppe Lattanzio and Marco Tripodi and Piero Musiani and Valeria Poli",

note = "Funding Information: We would like to thank Drs. P. Garside and F. Powrie for critically reading the manuscript. We are grateful to Mr. D. Lunny for help with keratin immunostaining, Drs. U. Betz and K. Rajewsky for providing the MX-Cre mouse transgenic line, Drs. F. Powrie, S. Cobbold, R.L.Coffman, S. Landolfo, and A. Vecchi for the gift of antibodies, Drs. P. Crocker and R. Porter for helpful advice and Mrs. L. Malone and V. Murray-Tait for expert mouse care. STAT3-targeted mice were generated at the Istituto di Biologia Molecolare I.R.B.M. P. Angeletti by V.P. and T.A. V.P. was supported by the Wellcome Trust, MIUR (Ministero dell'Istruzione, dell'Universit{\`a} e della Ricerca) and AIRC (Associazione Italiana Ricerca sul Cancro). T.A. was supported by Ministero della Sanit{\`a} (Ricerca Finalizzata), and was the recipient of an EC Marie Curie. E. Di C. was the recipient of a FIRC (Italian Foundation for Cancer Research) Post-doctoral fellowship.",

year = "2004",

month = apr,

day = "21",

doi = "10.1016/j.cyto.2003.12.002",

language = "English (US)",

volume = "26",

pages = "45--56",

journal = "Cytokine",

issn = "1043-4666",

publisher = "Academic Press",

number = "2",

}

TY - JOUR

T1 - Induced somatic inactivation of STAT3 in mice triggers the development of a fulminant form of enterocolitis

AU - Alonzi, Tonino

AU - Newton, Ian P.

AU - Bryce, Paul J.

AU - Di Carlo, Emma

AU - Lattanzio, Giuseppe

AU - Tripodi, Marco

AU - Musiani, Piero

AU - Poli, Valeria

N1 - Funding Information: We would like to thank Drs. P. Garside and F. Powrie for critically reading the manuscript. We are grateful to Mr. D. Lunny for help with keratin immunostaining, Drs. U. Betz and K. Rajewsky for providing the MX-Cre mouse transgenic line, Drs. F. Powrie, S. Cobbold, R.L.Coffman, S. Landolfo, and A. Vecchi for the gift of antibodies, Drs. P. Crocker and R. Porter for helpful advice and Mrs. L. Malone and V. Murray-Tait for expert mouse care. STAT3-targeted mice were generated at the Istituto di Biologia Molecolare I.R.B.M. P. Angeletti by V.P. and T.A. V.P. was supported by the Wellcome Trust, MIUR (Ministero dell'Istruzione, dell'Università e della Ricerca) and AIRC (Associazione Italiana Ricerca sul Cancro). T.A. was supported by Ministero della Sanità (Ricerca Finalizzata), and was the recipient of an EC Marie Curie. E. Di C. was the recipient of a FIRC (Italian Foundation for Cancer Research) Post-doctoral fellowship.

PY - 2004/4/21

Y1 - 2004/4/21

N2 - We have generated mice in which the gene encoding the transcription factor STAT3 can be inactivated in multiple cell types by triggering the endogenous production of type I interferon. Gene inactivation is particularly effective in the liver and the adipose tissue, as well as in macrophages and gut epithelial cells. Upon induction of the mutation, mice develop a wasting syndrome culminating in an aggressive and fatal form of enterocolitis, limited to the large intestine, within 2-3 weeks after the treatment. The disease is characterised by massive infiltration of the gut mucosa by macrophages, granulocytes and CD4+ cells, increased expression of endothelial adhesion molecules and high production of the cytokines interleukin (IL)-6, IL-12, interferon-γ and IL-10. IL-12 p40 plays a pivotal role in disease development as in vivo treatment with neutralising antibodies completely prevents its onset. Interestingly, oral treatment with wide spectrum antibiotics does not have any effect on either the onset or the development of colitis. Taken together, these data show that STAT3 plays a crucial role in the maintenance of intestinal homeostasis and possibly in mediating specialised cell functions in the intestinal epithelium.

AB - We have generated mice in which the gene encoding the transcription factor STAT3 can be inactivated in multiple cell types by triggering the endogenous production of type I interferon. Gene inactivation is particularly effective in the liver and the adipose tissue, as well as in macrophages and gut epithelial cells. Upon induction of the mutation, mice develop a wasting syndrome culminating in an aggressive and fatal form of enterocolitis, limited to the large intestine, within 2-3 weeks after the treatment. The disease is characterised by massive infiltration of the gut mucosa by macrophages, granulocytes and CD4+ cells, increased expression of endothelial adhesion molecules and high production of the cytokines interleukin (IL)-6, IL-12, interferon-γ and IL-10. IL-12 p40 plays a pivotal role in disease development as in vivo treatment with neutralising antibodies completely prevents its onset. Interestingly, oral treatment with wide spectrum antibiotics does not have any effect on either the onset or the development of colitis. Taken together, these data show that STAT3 plays a crucial role in the maintenance of intestinal homeostasis and possibly in mediating specialised cell functions in the intestinal epithelium.

KW - Conditional gene inactivation

KW - Enterocolitis

KW - Inflammation

KW - Inflammatory bowel disease

KW - STAT3

UR - http://www.scopus.com/inward/record.url?scp=1642619154&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=1642619154&partnerID=8YFLogxK

U2 - 10.1016/j.cyto.2003.12.002

DO - 10.1016/j.cyto.2003.12.002

M3 - Article

C2 - 15050604

AN - SCOPUS:1642619154

SN - 1043-4666

VL - 26

SP - 45

EP - 56

JO - Cytokine

JF - Cytokine

IS - 2

ER -

Induced somatic inactivation of STAT3 in mice triggers the development of a fulminant form of enterocolitis

Abstract

Funding

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this