Age associated differences in response to lipopolysaccharide: central role of TNF

Abstract

As Gram negative bacterial infection is a common cause of septic shock in the older population in the U.S., we employed an experimental model of Sepsis to study the cause of this increased lethality due to LPS in the older population. Studies on three different age groups of mice namely young (2 mo old), mature (12 mo old) and old (24 mo old) showed that the older mice were about ten times more sensitive to LPS. This difference in response to LPS did not result from an increase in either the LPS receptor number on macrophages or an increase in the levels of LPS binding proteins in these aged mice. TNF production in response to sublethal doses of LPS did not show a significant difference between the two groups, though for higher doses of LPS a siginificantly higher level of TNF was produced in the aged mice. Other cytokines namely IL-l(x and IFN-,Y seemed to have a lesser role to play than TNF in the age associated sensitivity to LPS seen in aged animals. Antibodies to TNF afforded protection to aged animals given a supralethal dose of LPS establishing the central role of TNF in the increased sensitivity to LPS seen in the aged animals. In vitro, in response to LPS, the macrophages from the two age groups produced equivalent amounts of cytokines. Glucocorticoids, natural inhibitors of cytokine production, were present at comparable levels in both age groups though the levels were maximized at a lower concentration of LPS in 24 mo old animals. Exogenous glucocorticoids were also effective in affording protection against lethal doses of LPS and this was accompanied by a decrease in the levels of cytokine production in these animals. Thus increased sensitivity to LPS observed in the aged animals seems to be primarily due to excessive production of TNF and the internal hormonal milieu seems to have a definite effect on the overproduction of this particular cytokine.