Posttranscriptional Suppression of Lipopolysaccharide-Stimulated Inflammatory Responses by Macrophages in Middle-Aged Mice : A Possible Role for Eukaryotic Initiation Factor 2α

Abstract EN

The intensities of macrophage inflammatory responses to bacterial components gradually decrease with age.

Given that a reduced rate of protein synthesis is a common age-related biochemical change, which is partially mediated by increased phosphorylation of eukaryotic initiation factor-2α (eIF-2α), we investigated the mechanism responsible for the deterioration of macrophage inflammatory responses, focusing specifically on the age-related biochemical changes in middle-aged mice.

Peritoneal macrophages isolated from 2-month-old (young) and 12-month-old (middle-aged) male BALB/c mice were stimulated with lipopolysaccharide (LPS).

Although LPS-stimulated secretion of tumor necrosis factor-α (TNF-α) by the macrophages from middle-aged mice was significantly lower than that from young mice, LPS caused marked increases in levels of TNF-α mRNA in macrophages from middle-aged as well as young mice.

Moreover, LPS evoked similar levels of phosphorylation of c-Jun N-terminal kinase (JNK) and nuclear factor-κB (NF-κB) in young and middle-aged mice.

In contrast, the basal level of phosphorylated eIF-2α in macrophages from middle-aged mice was higher than that in macrophages from young mice.

Salubrinal, an inhibitor of the phosphatase activity that dephosphorylates eIF-2α, suppressed the LPS-stimulated inflammatory responses in a murine macrophage cell line RAW264.7.

These results suggest that posttranscriptional suppression of macrophage inflammatory responses during middle age requires phosphorylation of eIF-2α.