ProNGF mediates death of Natural Killer cells through activation of the p75NTR-sortilin complex.
The common neurotrophin receptor P75NTR, its co-receptor sortilin and ligand proNGF, have not previously been investigated in Natural Killer (NK) cell function. We found freshly isolated NK cells express sortilin but not significant amounts of P75NTR unless exposed to interleukin-12 (IL-12), or cultured in serum free conditions, suggesting this receptor is sequestered. A second messenger associated with p75NTR, neurotrophin-receptor-interacting-MAGE-homologue (NRAGE) was identified in NK cells. Cleavage resistant proNGF123 killed NK cells in the presence of IL-12 after 20h and without IL-12 in serum free conditions at 48h. This was reduced by blocking sortilin with neurotensin. We conclude that proNGF induced apoptosis of NK cells may have important implications for limiting the innate immune response.
Rogers
Mary-Louise
ML
Department of Human Physiology, School of Medicine, Flinders University, GPO Box 2100 Adelaide 5001, Australia. mary-louise.rogers@flinders.edu.au
Bailey
Sheree
S
Matusica
Dusan
D
Nicholson
Ian
I
Muyderman
Hakan
H
Pagadala
Promila C
PC
Neet
Kenneth E
KE
Zola
Heddy
H
Macardle
Peter
P
Rush
Robert A
RA
D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000378:metabolism*; D015703:Antigens, CD / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects*; D005434:Flow Cytometry / Q000379:methods; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D007694:Killer Cells, Natural / Q000187:drug effects*; D008214:Lymphocytes / Q000145:classification / Q000187:drug effects / Q000378:metabolism; D020932:Nerve Growth Factor / Q000494:pharmacology*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D011498:Protein Precursors / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D020917:Receptor, trkA / Q000378:metabolism; D017475:Receptors, Nerve Growth Factor / Q000235:genetics / Q000378:metabolism*; D000099183:Sortilin
D033942:Adaptor Proteins, Vesicular Transport; D015703:Antigens, CD; D020932:Nerve Growth Factor; D009419:Nerve Tissue Proteins; D011498:Protein Precursors; D012333:RNA, Messenger; D020917:Receptor, trkA; D017475:Receptors, Nerve Growth Factor; D000099183:Sortilin; C484065:NGFR protein, human; C061397:pro-nerve growth factor, human