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Prepublished online as a Blood First Edition Paper on May 31, 2002; DOI 10.1182/blood-2002-01-0012.
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Blood, 1 October 2002, Vol. 100, No. 7, pp. 2330-2340
CHEMOKINES
Transgenic overexpression of human IL-17E results in
eosinophilia, B-lymphocyte hyperplasia, and altered antibody
production
Mee Rhan Kim,
Raffi Manoukian,
Richard Yeh,
Scott M. Silbiger,
Dimitry M. Danilenko,
Sheila Scully,
Jilin Sun,
Margaret L. DeRose,
Marina Stolina,
David Chang,
Gwyneth Y. Van,
Kristie Clarkin,
Hung Q. Nguyen,
Yan Bin Yu,
Shuqian Jing,
Giorgio Senaldi,
Gary Elliott, and
Eugene S. Medlock
From the Departments of Functional Genomics,
Pathology, Inflammation, Clinical Immunology, and Protein Science,
Amgen Inc, Thousand Oaks, California.
We have identified and cloned a novel human cytokine with homology
to cytokines of the interleukin-17 (IL-17) family, which we have termed
human IL-17E (hIL-17E). With the identification of several IL-17 family
members, it is critical to understand the in vivo function of these
molecules. We have generated transgenic mice overexpressing hIL-17E
using an apolipoprotein E (ApoE) hepatic promoter. These mice displayed
changes in the peripheral blood, particularly, a 3-fold increase in
total leukocytes consisting of increases in eosinophils, lymphocytes,
and neutrophils. Splenomegaly and lymphoadenopathy were predominant and
included marked eosinophil infiltrates and lymphoid hyperplasia.
CCR3+ eosinophils increased in the blood and lymph nodes of
the transgenic mice by 50- and 300-fold, respectively. Eosinophils also
increased 8- to 18-fold in the bone marrow and spleen, respectively. In the bone marrow, most of the eosinophils had an immature appearance. CD19+ B cells increased 2- to 5-fold in the peripheral
blood, 2-fold in the spleen, and 10-fold in the lymph nodes of
transgenic mice, whereas CD4+ T lymphocytes increased
2-fold in both blood and spleen. High serum levels of the cytokines
IL-2, IL-4, IL-5, granulocyte colony-stimulating factor, eotaxin, and
interferon  were observed. Consistent with B-lymphocyte increases,
serum immunoglobulin (Ig) M, IgG, and IgE were significantly elevated.
Antigenic challenge of the transgenic mice with keyhole limpet
hemocyanin (KLH) resulted in a decrease in anti-KLH IgG
accompanied by increases of anti-KLH IgA and IgE. In situ hybridization
of transgenic tissues revealed that IL-17Rh1 (IL-17BR/Evi27), a
receptor that binds IL-17E, is up-regulated. Taken together, these data
indicate that IL-17E regulates hematopoietic and immune functions,
stimulating the development of eosinophils and B lymphocytes. The fact
that hIL-17E overexpression results in high levels of circulating
eosinophils, IL-4, IL-5, eotaxin, and IgE suggests that IL-17E may be a
proinflammatory cytokine favoring Th2-type immune responses.
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