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Prepublished online as a Blood First Edition Paper on May 31, 2002; DOI 10.1182/blood-2002-01-0012.
Submitted January 3, 2002
Accepted April 16, 2002
Transgenic overexpression of human IL-17E results in eosinophilia, B lymphocyte hyperplasia, and altered antibody production
Mee R Kim, Raffi Manoukian, Richard Yeh, Scott M Silbiger, Dimitry M Danilenko, Sheila Scully, Jilin Sun, Margaret L De Rose, Marina Stolina, David Chang, Gwyneth Y Van, Kristie Clarkin, Hung Q Nguyen, Yan B Yu, Shuqian Jing, Giorgio Senaldi, Gary Elliott, and Eugene S Medlock*
Department of Functional Genomics, Amgen Inc, Thousand Oaks, CA, USA
Department of Pathology, Amgen Inc, Thousand Oaks, CA, USA
Department of Protein Science, Amgen Inc, Thousand Oaks, CA, USA
Department of Inflammation, Amgen Inc, Thousand Oaks, CA, USA
Department of Clinical Immunology, Amgen Inc, Thousand Oaks, CA, USA
* Corresponding author; email: emedlock{at}amgen.com.
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 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-fold 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, while CD4+ T lymphocytes increased 2-fold in both blood and spleen. High serum levels of the cytokines IL-2, IL-4, IL-5, G-CSF, eotaxin, and IFN- were observed. Consistent with B lymphocyte increases, serum IgM, IgG, and IgE were significantly elevated. Antigenic challenge of the transgenic mice with 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 which binds IL-17E, is upregulated. 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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