IL-15, a survival factor for kidney epithelial cells, counteracts apoptosis and inflammation during nephritis.
IL-15, a T cell growth factor, has been linked to exacerbating autoimmune diseases and allograft rejection. To test the hypothesis that IL-15-deficient (IL-15-/-) mice would be protected from T cell-dependent nephritis, we induced nephrotoxic serum nephritis (NSN) in IL-15-/- and wild-type (IL-15+/+) C57BL/6 mice. Contrary to our expectations, IL-15 protects the kidney during this T cell-dependent immunologic insult. Tubular, interstitial, and glomerular pathology and renal function are worse in IL-15-/- mice during NSN. We detected a substantial increase in tubular apoptosis in IL-15-/- kidneys. Moreover, macrophages and CD4 T cells are more abundant in the interstitia and glomeruli in IL-15-/- mice. This led us to identify several mechanisms responsible for heightened renal injury in the absence of IL-15. We now report that IL-15 and the IL-15 receptor (alpha, beta, gamma chains) are constitutively expressed in normal tubular epithelial cells (TECs). IL-15 is an autocrine survival factor for TECs. TEC apoptosis induced with anti-Fas or actinomycin D is substantially greater in IL-15-/- than in wild-type TECs. Moreover, IL-15 decreases the induction of a nephritogenic chemokine, MCP-1, that attracts leukocytes into the kidney during NSN. Taken together, we suggest that IL-15 is a therapeutic for tubulointerstitial and glomerular kidney diseases.
Shinozaki
Michiya
M
Laboratory of Molecular Autoimmune Disease, Renal Division, Brigham and Women's Hospital, Boston, Massachusetts, USA.
Hirahashi
Junichi
J
Lebedeva
Tatiana
T
Liew
Foo Y
FY
Salant
David J
DJ
Maron
Ruth
R
Kelley
Vicki Rubin
VR
D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D002470:Cell Survival; D018932:Chemokine CCL2 / Q000235:genetics; D003609:Dactinomycin / Q000494:pharmacology; D015536:Down-Regulation; D004847:Epithelial Cells / Q000166:cytology / Q000276:immunology; D015870:Gene Expression; D007132:Immunoglobulin Isotypes; D019409:Interleukin-15 / Q000235:genetics / Q000276:immunology*; D007668:Kidney / Q000166:cytology / Q000276:immunology / Q000293:injuries*; D007684:Kidney Tubules / Q000276:immunology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009395:Nephritis, Interstitial / Q000276:immunology*; D053647:Receptors, Interleukin-15; D015375:Receptors, Interleukin-2 / Q000235:genetics; D012756:Sheep; D019014:fas Receptor / Q000276:immunology
D018932:Chemokine CCL2; C508025:Il15ra protein, mouse; D007132:Immunoglobulin Isotypes; D019409:Interleukin-15; D053647:Receptors, Interleukin-15; D015375:Receptors, Interleukin-2; D019014:fas Receptor; D003609:Dactinomycin