Heat shock protein 60 is released in immune-mediated glomerulonephritis and aggravates disease: in vivo evidence for an immunologic danger signal.
Heat shock proteins (Hsp) are ubiquitous intracellular proteins that can be released in various forms of cellular stress. Some Hsp, such as Hsp60, have been shown to stimulate directly T cell-mediated immune responses in vitro. Here, it is demonstrated that Hsp60 is released from the kidneys and excreted into the urine of mice with nephrotoxic nephritis (NTN), a model of rapidly progressive glomerulonephritis. For examining the functional relevance of Hsp60 release, this protein was injected into mice with subnephritogenic NTN, in which only transient proteinuria and minimal organ damage occur that do not progress to terminal kidney failure. Injection of Hsp60 strikingly aggravated disease, as evidenced by global glomerular necrosis, tubulointerstitial damage, and complete anuria after 10 to 12 d. This effect was mediated neither by endotoxin contaminations of Hsp60 nor by autologous antibodies. It was strictly T cell dependent but not associated with a systemic Th1/Th2 shift. Thus, Hsp60 is an endogenous mediator stimulating immune effector mechanisms that contribute to the progression of NTN. These findings demonstrate in vivo that Hsp60 fulfills criteria of immunologic danger signals and suggest that such signals may be involved in immune-mediated kidney disease.
Lang
Andreas
A
Institute of Molecular Medicine and Experimental Immunology, Friedrich-Wilhelms-Universität, 53105 Bonn, Germany.
Benke
Dirk
D
Eitner
Frank
F
Engel
Daniel
D
Ehrlich
Svenja
S
Breloer
Minka
M
Hamilton-Williams
Emma
E
Specht
Sabine
S
Hoerauf
Achim
A
Floege
Jürgen
J
von Bonin
Arne
A
Kurts
Christian
C
D000818:Animals; D015415:Biomarkers / Q000097:blood*; D001707:Biopsy, Needle; D015153:Blotting, Western; D018834:Chaperonin 60 / Q000032:analysis / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D005434:Flow Cytometry; D005921:Glomerulonephritis / Q000276:immunology* / Q000473:pathology*; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D012016:Reference Values; D012307:Risk Factors; D012680:Sensitivity and Specificity
D015415:Biomarkers; D018834:Chaperonin 60