title: Functional role of kallikrein 6 in regulating immune cell survival.
abstract: BACKGROUND
  Kallikrein 6 (KLK6) is a newly identified member of the kallikrein family of secreted serine proteases that prior studies indicate is elevated at sites of central nervous system (CNS) inflammation and which shows regulated expression with T cell activation. Notably, KLK6 is also elevated in the serum of multiple sclerosis (MS) patients however its potential roles in immune function are unknown. Herein we specifically examine whether KLK6 alters immune cell survival and the possible mechanism by which this may occur.
  
  
  RESULTS
  Using murine whole splenocyte preparations and the human Jurkat T cell line we demonstrate that KLK6 robustly supports cell survival across a range of cell death paradigms. Recombinant KLK6 was shown to significantly reduce cell death under resting conditions and in response to camptothecin, dexamethasone, staurosporine and Fas-ligand. Moreover, KLK6-over expression in Jurkat T cells was shown to generate parallel pro-survival effects. In mixed splenocyte populations the vigorous immune cell survival promoting effects of KLK6 were shown to include both T and B lymphocytes, to occur with as little as 5 minutes of treatment, and to involve up regulation of the pro-survival protein B-cell lymphoma-extra large (Bcl-XL), and inhibition of the pro-apoptotic protein Bcl-2-interacting mediator of cell death (Bim). The ability of KLK6 to promote survival of splenic T cells was also shown to be absent in cell preparations derived from PAR1 deficient mice.
  
  
  CONCLUSIONS
  KLK6 promotes lymphocyte survival by a mechanism that depends in part on activation of PAR1. These findings point to a novel molecular mechanism regulating lymphocyte survival that is likely to have relevance to a range of immunological responses that depend on apoptosis for immune clearance and maintenance of homeostasis.
authors.affiliation: Neurobiology of Disease Program, Mayo Medical and Graduate School, Rochester, Minnesota, United States of America. Scarisbrick.Isobel@Mayo.edu
authors.forename: Isobel A
authors.initials: IA
authors.lastname: Scarisbrick
authors.forename: Benjamin
authors.initials: B
authors.lastname: Epstein
authors.forename: Beth A
authors.initials: BA
authors.lastname: Cloud
authors.forename: Hyesook
authors.initials: H
authors.lastname: Yoon
authors.forename: Jianmin
authors.initials: J
authors.lastname: Wu
authors.forename: Danielle N
authors.initials: DN
authors.lastname: Renner
authors.forename: Sachiko I
authors.initials: SI
authors.lastname: Blaber
authors.forename: Michael
authors.initials: M
authors.lastname: Blaber
authors.forename: Alexander G
authors.initials: AG
authors.lastname: Vandell
authors.forename: Alexandra L
authors.initials: AL
authors.lastname: Bryson
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D019169:Jurkat Cells; D007610:Kallikreins / Q000494:pharmacology*; D008214:Lymphocytes / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D044463:Receptor, PAR-1 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013154:Spleen / Q000166:cytology; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism
chemical_list: D019253:Proto-Oncogene Proteins c-bcl-2; D044463:Receptor, PAR-1; D011065:Poly(ADP-ribose) Polymerases; C103551:KLK6 protein, human; D007610:Kallikreins