Elevated expression of transmembrane IL-15 in immune cells correlates with the development of murine lupus: a potential target for immunotherapy against SLE.
Presentation in trans by the Interleukin-15 receptor alpha chain (IL-15Ralpha) has been suggested as the main mechanism for IL-15 anchoring to the cell surface, but it is also evident that IL-15 can exist as a transmembrane protein. We herein demonstrate that replacement of the first 41 residues of human IL-15 (hIL-15) with Igkappa chain leader sequence resulted in secretion of most of the recombinant hIL-15 expressed in transfectant cells, thus identifying the transmembrane region of IL-15. A fusion protein (hIL-15Ralpha-Fc) between the extracellular domain of hIL-15Ralpha and the Fc fragment of IgG1 was prepared and shown to be able to bind with transmembrane IL-15 (tmIL-15). The level of tmIL-15 expression in macrophages, activated T cells and B cells from 6-month-old BXSB male mice, an animal model for systemic lupus erythematosus (SLE), was significantly increased compared with that from BXSB females or young males. In addition, hIL-15Ralpha-Fc was able to block the T cell stimulating and anti-apoptotic effect of the tmIL-15-positive BXSB macrophages in vitro. Intravenous administration of hIL-15Ralpha-Fc reduced the titre of autoantibodies against dsDNA and also proteinuria in aged BXSB males, implying that neutralization of IL-15 activity in vivo may be an effective way of treating SLE.
Bo
H
H
Department of Immunology, Peking University Health Science Center, Peking University, Beijing, China.
Wei
X-Q
XQ
Dong
H
H
Zhang
Y
Y
Lv
P
P
Liu
W
W
Koutoulaki
A
A
Gao
X-M
XM
D000818:Animals; D017209:Apoptosis; D019556:COS Cells; D002522:Chlorocebus aethiops; D005260:Female; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000096:biosynthesis; D019409:Interleukin-15 / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000502:physiology*; D008180:Lupus Erythematosus, Systemic / Q000209:etiology* / Q000276:immunology / Q000628:therapy; D008213:Lymphocyte Activation; D008264:Macrophages / Q000502:physiology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D053647:Receptors, Interleukin-15 / Q000096:biosynthesis / Q000627:therapeutic use; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000627:therapeutic use
D007141:Immunoglobulin Fc Fragments; D019409:Interleukin-15; D053647:Receptors, Interleukin-15; D011993:Recombinant Fusion Proteins