Forced expression of murine IL-17E induces growth retardation, jaundice, a Th2-biased response, and multiorgan inflammation in mice.
IL-17 is a proinflammatory cytokine, and its in vivo expression induces neutrophilia in mice. IL-17E is a recently described member of an emerging family of IL-17-related cytokines. IL-17E has been shown to bind IL-17Rh1, a protein distantly related to the IL-17R, suggesting that IL-17E probably possesses unique biological functions. In this study, we have identified the murine ortholog of IL-17E and developed transgenic mice to characterize its actions in vivo. Biological consequences of overexpression of murine (m)IL-17E, both unique to IL-17E and similar to IL-17, were revealed. Exposure to mIL-17E resulted in a Th2-biased response, characterized by eosinophilia, increased serum IgE and IgG1, and a Th2 cytokine profile including elevated serum levels of IL-13 and IL-5 and elevated gene expression of IL-4, IL-5, IL-10, and IL-13 was observed in many tissues. Increased gene expression of IFN-gamma in several tissues and elevated serum TNF-alpha were also noted. In addition, IL-17E induces G-CSF production in vitro and mIL-17E-transgenic mice had increased serum G-CSF and exhibit neutrophilia, a property shared by IL-17. Moreover, exposure to mIL-17E elicited pathological changes in multiple tissues, particularly liver, heart, and lungs, characterized by mixed inflammatory cell infiltration, epithelial hyperplasia, and hypertrophy. Taken together, these findings suggest that IL-17E is a unique pleiotropic cytokine and may be an important mediator of inflammatory and immune responses.
Pan
G
G
Department of Molecular Oncology, Genentech, Inc., South San Francisco, CA 94080, USA. jgpan@gene.com
French
D
D
Mao
W
W
Maruoka
M
M
Risser
P
P
Lee
J
J
Foster
J
J
Aggarwal
S
S
Nicholes
K
K
Guillet
S
S
Schow
P
P
Gurney
A L
AL
D016475:3T3 Cells; D000595:Amino Acid Sequence; D000818:Animals; D015815:Cell Adhesion Molecules / Q000096:biosynthesis; D054360:Chemokine CXCL1; D019743:Chemokines, CXC; D002630:Chemotactic Factors / Q000096:biosynthesis; D003001:Cloning, Molecular; D016207:Cytokines / Q000096:biosynthesis* / Q000235:genetics* / Q000302:isolation & purification / Q000502:physiology; D004802:Eosinophilia / Q000235:genetics / Q000276:immunology; D005786:Gene Expression Regulation / Q000276:immunology; D016179:Granulocyte Colony-Stimulating Factor / Q000096:biosynthesis; D006130:Growth Disorders / Q000235:genetics* / Q000276:immunology*; D006133:Growth Substances / Q000096:biosynthesis; D006801:Humans; D007073:Immunoglobulin E / Q000097:blood; D007074:Immunoglobulin G / Q000097:blood; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000473:pathology; D036341:Intercellular Signaling Peptides and Proteins; D018793:Interleukin-13 / Q000097:blood; D020381:Interleukin-17 / Q000096:biosynthesis* / Q000235:genetics* / Q000302:isolation & purification / Q000502:physiology; D015848:Interleukin-5 / Q000097:blood; D007565:Jaundice / Q000201:enzymology / Q000235:genetics* / Q000276:immunology*; D007964:Leukocytosis / Q000235:genetics / Q000276:immunology; D008099:Liver / Q000201:enzymology; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009504:Neutrophils / Q000276:immunology / Q000473:pathology; D009928:Organ Specificity / Q000235:genetics / Q000276:immunology; D051381:Rats; D018418:Th2 Cells / Q000276:immunology*
C475829:CXCL1 protein, human; D015815:Cell Adhesion Molecules; D054360:Chemokine CXCL1; D019743:Chemokines, CXC; D002630:Chemotactic Factors; C475895:Cxcl1 protein, mouse; C513297:Cxcl1 protein, rat; D016207:Cytokines; D006133:Growth Substances; D007074:Immunoglobulin G; D036341:Intercellular Signaling Peptides and Proteins; D018793:Interleukin-13; D020381:Interleukin-17; D015848:Interleukin-5; D016179:Granulocyte Colony-Stimulating Factor; D007073:Immunoglobulin E