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 (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 gamma 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.
Kim
Mee Rhan
MR
Departments of Functional Genomics, Pathology, Inflammation, Clinical Immunology, and Protein Science, Amgen Inc, Thousand Oaks, California 91302, USA. mkim@amgen.com
Manoukian
Raffi
R
Yeh
Richard
R
Silbiger
Scott M
SM
Danilenko
Dimitry M
DM
Scully
Sheila
S
Sun
Jilin
J
DeRose
Margaret L
ML
Stolina
Marina
M
Chang
David
D
Van
Gwyneth Y
GY
Clarkin
Kristie
K
Nguyen
Hung Q
HQ
Yu
Yan Bin
YB
Jing
Shuqian
S
Senaldi
Giorgio
G
Elliott
Gary
G
Medlock
Eugene S
ES
D000595:Amino Acid Sequence; D000818:Animals; D000917:Antibody Formation / Q000235:genetics*; D018941:Antigens, CD19 / Q000032:analysis; D001402:B-Lymphocytes / Q000276:immunology* / Q000473:pathology; D001483:Base Sequence; D003001:Cloning, Molecular; D016207:Cytokines / Q000235:genetics* / Q000276:immunology; D004802:Eosinophilia / Q000235:genetics / Q000276:immunology*; D006801:Humans; D006965:Hyperplasia; D016130:Immunophenotyping; D020381:Interleukin-17 / Q000235:genetics* / Q000276:immunology; D008198:Lymph Nodes / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009929:Organ Size; D012333:RNA, Messenger / Q000235:genetics; D011994:Recombinant Proteins / Q000276:immunology; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D013154:Spleen / Q000033:anatomy & histology / Q000276:immunology; D014158:Transcription, Genetic
D018941:Antigens, CD19; D016207:Cytokines; D020381:Interleukin-17; D012333:RNA, Messenger; D011994:Recombinant Proteins