Overactivity of Tumor Necrosis Factor-Alpha but Not Interleukin 6 Is Associated with Low Natural Killer Cytotoxic Activity in the Elderly

Abstract

In this paper we asked whether the increased production of two proinflammatory cytokines – tumor necrosis factor-α (TNFα) and interleukin-6 (IL6) in the absence of the inflammatory stimulus, a phenomenon frequently occurring in the elderly, may contribute to the decrease of natural killer (NK) cytotoxic activity. NK cell activity is a part of a nonspecific immunity directed against infected and transformed cells. We measured the levels of bioactive TNFα and IL6 during cytotoxic NK reactions and analyzed the effect of neutralizing monoclonal antibodies anti-TNFα and anti-IL6 on the outcome of cytotoxic reaction. Bioactive TNFα was produced in higher amounts during cytotoxic reactions of the elderly with low NK activity in comparison with its production by the elderly with high NK activity. Anti-TNFα decreased already low cytotoxic responses of the elderly while not having an effect on the cytotoxic potential of high responders. More of the bioactive IL6 was released during cytotoxic reactions of the elderly as compared with young people. There was, however, no relation between the height of NK cytotoxic activity and the amount of IL6. Our results suggest that the increased level of TNFα seen in the elderly low NK responders may pose a compensatory mechanism, necessary to keep the highest possible level of NK responses. The increased bioactivity of IL6 during NK reaction of the elderly does not seem to participate in the regulation of the level of NK cytotoxic activity.

Natural Killer Activity and Thyroid Hormone Levels in Young and Elderly Persons

“…Nevertheless, we found that even in the population of apparently healthy old people (who did not, however, fulfil all SP criteria), NK activity was lower than that in young people [7]. These observations suggested that additional factors, and not only old age per se, could be responsible for the age-related preponderance of low NK activity in the healthy elderly.…”

“…cytokines, may significantly contribute to this phenomenon. We have recently observed that low NK cytotoxic activity in the elderly was associated with a lack of full health and overactivity of tumor necrosis factor · (TNF·) but not interleukin-6 (IL-6) [7,20]. Interestingly, it has been shown that decreased serum T 3 levels correlate with increased plasma concentration of TNF· [21] and IL-2 [22] in old patients with nonthyroid illness.…”

“…After three washings with phosphate-buffered saline the cells were suspended in culture medium RPMI 1640 (Life Sciences, Warsaw, Poland) supplemented with 5% fetal calf serum (FCS; Serva, Warsaw, Poland). Assessment of NK Cytotoxic Activity NK cytotoxic activity was measured by a standard ( 51 Cr) chromium release assay as described previously [7]. K562 (human erythroleukemic cell line NK-sensitive) cells were used as targets.…”

“…Definition of 'Low' and 'High' NK Activity NK activity in our study was arbitrarily designated as high or low on the basis of our long-term experience measuring NK activity in more than 600 elderly people [5][6][7]9]. The cutoff level for defining low and high responses was set at the value of 20%.…”

“…The immunological status of the elderly is characterized by the impairment of cell-mediated immunity that is reflected in decreased proliferative responses to T cell [1] and B cell [1, 2] mitogens. However, natural killer (NK) activity, an important component of antiviral and antitumor immunity, has been found to be unchanged [3], increased [4] or dependent on the health status [5][6][7] during physiological aging. In an attempt to resolve these dis-…”