Role of inositol 1,4,5-triphosphate and p38 mitogen-activated protein kinase in reactive oxygen species generation by granulocytes in a cyclic AMP-dependent manner: an age-related phenomenon.
BACKGROUND
It is generally agreed that elderly subjects undergo progressive deterioration of their immune responsiveness, which leads to an increased susceptibility to autoimmune processes, neoplasm and inflammation. Thus there is a general consensus that regulation of inflammation results from a balance between pro-inflammatory and anti-inflammatory pathways.


OBJECTIVE
The present study aimed to investigate the possible alterations of cyclic AMP/protein kinase A (cAMP/PKA) and p38 mitogen-activated protein kinase (p38 MAPK) pathway signaling (reactive oxygen species (ROS) generation) and inositol 1,4,5-triphosphate (InsP3) production by neutrophils during the aging process.


METHODS
Age-induced ROS generation and InsP3 production were studied in healthy subjects ranging in age from 20 to 80 years. The subjects were divided into six age groups: (I) 20-29, (II) 30-39, (III) 40-49, (IV) 50-59, (V) 60-69, and (VI) 70-80 years old. The effect of cAMP, H89 (inhibitor PKA), and PD169316 (inhibitor p38 MAPK) on ROS production was quantified in a luminol-dependent chemiluminescence assay (relative light units/min) and by InsP3 release (cpm).


RESULTS
Our results demonstrated a lack of dibutyryl cAMP inhibitory effects on ROS generation and InsP3 production by granulocytes from PKA-dependent 50-year-olds. However, the inhibitory effect of cAMP is restored in neutrophils after the age of 50 years when p38 MAPK signaling is inhibited.


CONCLUSIONS
The present study may be important towards a better understanding of the high susceptibility to infections and age-related inflammatory and deregulation diseases. The alteration of cAMP/PKA and p38 MAPK signaling pathways enhances the inflammatory process.
Chaves
Míriam Martins
MM
Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
Costa
Daniela Caldeira
DC
Pereira
Cristina Costa Telhado
CC
Andrade
Thiago Rabelo
TR
Horta
Bernardo Coelho
BC
Nogueira-Machado
José Augusto
JA
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005260:Female; D006801:Humans; D007249:Inflammation; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009504:Neutrophils / Q000201:enzymology / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
D017382:Reactive Oxygen Species; D015544:Inositol 1,4,5-Trisphosphate; D017868:Cyclic AMP-Dependent Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases