Transgenic overexpression of human IL-17E results in eosinophilia, B-lymphocyte hyperplasia, and altered antibody production

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 (hIL17E). 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. Splenomegally and lymphoadenopathy were predominant and Included marked eosinophil Infiltrates and lymphoid hyperplasla. 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 gamma were observed. Consistent with B-lymphocyte increases, serum immunoglobulin (1g) 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-11 7Rh1 (IL-17BR/Ev127), 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. (C) 2002 by The American Society of Hematology.