T-kininogen, a cystatin-like molecule, inhibits ERK-dependent lymphocyte proliferation.
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.
Acuña-Castillo
Claudio
C
Instituto de Ciencias Biomédicas, Programa de Biología Celular y Molecular, Facultad de Medicina, Universidad de Chile, Independencia 1027, Santiago, Chile.
Aravena
Mauricio
M
Leiva-Salcedo
Elías
E
Pérez
Viviana
V
Gómez
Christian
C
Sabaj
Valeria
V
Nishimura
Sumiyo
S
Pérez
Claudio
C
Colombo
Alicia
A
Walter
Robin
R
Sierra
Felipe
F
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
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