Granulysin, a cytolytic molecule, is also a chemoattractant and proinflammatory activator.
Granulysin, a cationic protein produced by activated human CTL and NK cells, is cytolytic against microbial and tumor targets. In this study we show that granulysin also functions as a chemoattractant and activates monocytes to produce cytokines/chemokines. Although granulysin-mediated cytotoxicity occurs at micromolar concentrations, chemoattraction occurs in the nanomolar range, and immune activation occurs over a wide range of concentrations (nanomolar to micromolar). Granulysin causes a 2- to 7-fold increase in chemotaxis of monocytes, CD4(+), and CD8(+) memory (CD45RO) but not naive (CD45RA) T cells, NK cells, and mature, but not immature, monocyte-derived dendritic cells. Pertussis toxin treatment abrogates chemoattraction by granulysin, indicating involvement of G-protein-coupled receptor(s). At low concentrations (10 nM), granulysin promotes a 3- to 10-fold increase in MCP-1 and RANTES produced by monocytes and U937 cells, while a 2-fold increase in TNF-alpha production by LPS-stimulated monocytes requires higher concentrations of granulysin (micromolar). Taken together, these data indicate that the local concentration of granulysin is critical for the biologic activity, with high concentrations resulting in cytotoxicity while lower concentrations, presumably further from the site of granulysin release, actively recruit immune cells to sites of inflammation.
Deng
Anmei
A
Division of Immunology and Transplantation Biology, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, USA.
Chen
Sunxiao
S
Li
Qing
Q
Lyu
Shu-Chen
SC
Clayberger
Carol
C
Krensky
Alan M
AM
D000945:Antigens, Differentiation, T-Lymphocyte / Q000502:physiology* / Q000633:toxicity*; D001402:B-Lymphocytes / Q000276:immunology / Q000473:pathology; D002460:Cell Line; D002464:Cell Migration Inhibition; D002630:Chemotactic Factors / Q000502:physiology* / Q000633:toxicity; D002634:Chemotaxis, Leukocyte / Q000276:immunology; D003602:Cytotoxicity, Immunologic; D003713:Dendritic Cells / Q000276:immunology / Q000473:pathology; D006801:Humans; D018836:Inflammation Mediators / Q000502:physiology* / Q000633:toxicity; D007694:Killer Cells, Natural / Q000276:immunology / Q000473:pathology; D009000:Monocytes / Q000276:immunology / Q000473:pathology; D037342:Pertussis Toxin / Q000494:pharmacology; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000633:toxicity; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology; D020298:U937 Cells
D000945:Antigens, Differentiation, T-Lymphocyte; D002630:Chemotactic Factors; C075005:GNLY protein, human; D018836:Inflammation Mediators; D011994:Recombinant Proteins; D037342:Pertussis Toxin