Impaired interleukin-12-dependent T-cell functions during aging: role of signal transducer and activator of transcription 4 (STAT4) and suppressor of cytokine signaling 3 (SOCS3).
Interleukin (IL)-12 is the major inducer of T helper cell (Th) 1-type responses. Despite a higher IL-12 production, phytohemagglutinin (PHA)-stimulated peripheral blood mononuclear cells (PBMC), as well as CD4(+) or CD8(+) T cells from elderly donors released interferon (IFN)-gamma amounts similar to those observed in young controls, and underwent only a slight increase in IFN-gamma production after IL-12 costimulation. These findings were not due to an age-related reduction in IL-12 receptor expression. Interestingly, no difference in PHA-triggered signal transducer and activator of transcription 4 (STAT4) phosphorylation between young and elderly donors was found, and a significant IL-12-induced STAT4 activation occurred only in PHA-preactivated cells from the younger group. The age-related defect in IL-12 signaling was STAT4-restricted as it did not involve the p38 mitogen-activated protein kinase (MAPK) pathway. Finally, suppressor of cytokine signaling 3 (SOCS3) expression was significantly higher in unstimulated cells from elderly individuals, and it did not diminish after cell stimulation. These results indicate that a defective STAT4 activation, likely dependent on elevated SOCS3 levels, is involved in the impaired IL-12-dependent T-cell functions with aging.
Tortorella
Cosimo
C
Department of Internal Medicine, Immunology and Infectious Diseases, Section of Internal Medicine, University of Bari Medical School, Policlinico, 70124 Bari, Italy. c.tortorella@intmed.uniba.it
Stella
Isabella
I
Piazzolla
Giuseppina
G
Cappiello
Valentina
V
Simone
Olivia
O
Pisconti
Addolorata
A
Antonaci
Salvatore
S
D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000502:physiology*; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D018664:Interleukin-12 / Q000502:physiology*; D008297:Male; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D010766:Phosphorylation; D010835:Phytohemagglutinins / Q000494:pharmacology; D050797:STAT4 Transcription Factor / Q000502:physiology*; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000502:physiology*; D006377:T-Lymphocytes, Helper-Inducer / Q000502:physiology*
D010835:Phytohemagglutinins; C106644:SOCS3 protein, human; D050797:STAT4 Transcription Factor; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D018664:Interleukin-12; D020929:Mitogen-Activated Protein Kinase Kinases