title: T-kininogen, a cystatin-like molecule, inhibits ERK-dependent lymphocyte proliferation.
abstract: Plasma levels of kininogens increase with age in both rats and humans. Kininogens are inhibitors of cysteine proteinases, and filarial cysteine proteinase inhibitors (cystatins) reduce the proliferation of T cells. We evaluated whether T-kininogen (T-KG) might mimic this effect, and here we present data indicating that exposure of either rat splenocytes or Jurkat cells to purified T-KG results in inhibition of both ERK activation and [(3)H]-thymidine incorporation, both basal and in response to ConA or PHA. Interestingly, T-KG did not impair [(3)H]-thymidine incorporation in response to IL-2, which requires primarily the activation of the JNK and Jak/STAT pathways. These effects were neither the consequence of increased cell death, nor required the activity of kinin receptors. Furthermore, when T cell receptor proximal events were bypassed by the use of PMA plus Calcium ionophore, T-KG no longer inhibited ERK activation, suggesting that inhibition occurs upstream of these events, possibly at the level of membrane associated signal transduction molecules. We conclude that, like filarial cystatins, T-KG inhibits ERK-dependent T cell proliferation, and these observations suggest a possible role for T-KG in immunosenescence.
authors.affiliation: Instituto de Ciencias Biomédicas, Programa de Biología Celular y Molecular, Facultad de Medicina, Universidad de Chile, Independencia 1027, Santiago, Chile.
authors.forename: Claudio
authors.initials: C
authors.lastname: Acuña-Castillo
authors.forename: Mauricio
authors.initials: M
authors.lastname: Aravena
authors.forename: Elías
authors.initials: E
authors.lastname: Leiva-Salcedo
authors.forename: Viviana
authors.initials: V
authors.lastname: Pérez
authors.forename: Christian
authors.initials: C
authors.lastname: Gómez
authors.forename: Valeria
authors.initials: V
authors.lastname: Sabaj
authors.forename: Sumiyo
authors.initials: S
authors.lastname: Nishimura
authors.forename: Claudio
authors.initials: C
authors.lastname: Pérez
authors.forename: Alicia
authors.initials: A
authors.lastname: Colombo
authors.forename: Robin
authors.initials: R
authors.lastname: Walter
authors.forename: Felipe
authors.initials: F
authors.lastname: Sierra
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002118:Calcium / Q000737:chemistry / Q000378:metabolism; D016923:Cell Death; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003208:Concanavalin A / Q000494:pharmacology; D015891:Cystatins / Q000378:metabolism*; D003546:Cysteine Endopeptidases / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D006801:Humans; D007376:Interleukin-2 / Q000378:metabolism; D007476:Ionophores / Q000494:pharmacology; D019169:Jurkat Cells; D007704:Kininogens / Q000378:metabolism / Q000502:physiology*; D008214:Lymphocytes / Q000166:cytology*; D016393:Lymphoma, B-Cell / Q000378:metabolism; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D020935:MAP Kinase Signaling System; D051381:Rats; D015398:Signal Transduction; D013154:Spleen / Q000166:cytology; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology; D013936:Thymidine / Q000737:chemistry; D013997:Time Factors
chemical_list: D015891:Cystatins; D007376:Interleukin-2; D007476:Ionophores; D007704:Kininogens; D003208:Concanavalin A; D048049:Extracellular Signal-Regulated MAP Kinases; D048670:MAP Kinase Kinase 4; D003546:Cysteine Endopeptidases; D002118:Calcium; D013936:Thymidine