Interaction of Cytokines and Functional Status

Recently, a body of evidence has emerged suggesting that functional decline is associated with an excess production of cytokines. Cytokines are cell-associated proteins produced and secreted by inflammatory cells. They have the capacity to act at low concentrations on other cells, both locally and systematically, via specific cell receptors. Cytokines act principally in a paracrine fashion, and their concentrations in tissues are often several times higher than those found in the peripheral circulation.

Aging is characterised by a progressive increase in the concentrations of glucocorticoids and catecholamines and a decrease in the production of growth and sex hormones - a pattern reminiscent of that seen in chronic stress. Plasma levels of interleukin (IL)-6 increase with age, probably as the result of catecholamine hypersecretion and sex-steroid hyposecretion. However, age-associated changes in cytokine production are inconsistent [41].

Cohen and Pieper found that IL-6 levels correlate with the functional disability of the communi ty-dwelling elderly [42]. Therefore, IL-6 may contribute to the increased morbidity and mortality seen in chronically stressed or physiologically aged persons. Interleukin-6 and D-dimer levels have been associated with subsequent mortality and a decline in functional status. The relative risk of mortality increases to 1.28 (95% confidence interval [CI]: 0.98-1.69) for individuals with only IL-6 levels in the highest quartile, 1.53 (95% CI: 1.18-1.97) for those with only D-dimer levels in the highest quartile, and 2.00 (95% CI: 1.53-2.62) for those with levels of both in the highest quar-tile. Subjects with both high IL-6 and high D-dimer levels had the greatest declines in all measures of functional status [43].

In highly functioning, healthy, nondisabled older persons, a baseline measurement of serum albumin and plasma IL-6 was associated with 4-year mortality. In those subjects without evidence of IL-6-mediated inflammation, a lower albumin was associated with an adjusted relative risk of 2.1 for mortality, compared with subjects with higher albumin. In the presence of elevated IL-6 levels, both higher and lower serum albumin levels had similar risks (adjusted relative risks 4.0 and 3.8, respectively) compared with persons having a higher albumin and low IL-6. Higher serum albumin levels may have a protective effect in healthy older persons who do not have evidence of cytokine-mediated inflammation. This protective effect is not apparent in the presence of inflammation [44].

Older women with high IL-6 serum levels have a higher risk of developing physical disability and experience a steeper decline in walking ability than those with lower levels [45]. Older women in the highest IL-6 tertile were 1.76 (95% CI: 1.17-2.64) times more likely to develop disability due to mobility impairment and 1.62 (95% CI: 1.02-2.60) times more likely to develop mobility impairment and disability with respect to ADL . The increased risk of disability associated with IL-6 concentration was nonlinear, with the risk rising rapidly beyond plasma levels of 2.5 pg/ml. The effect of IL-6 on muscle atrophy may be a direct effect on muscles and/or due to the pathophysio-logic role played by IL-6 in specific diseases [46].

In congestive heart failure (CHF) patients, ele vated plasma cytokine levels are associated with worse functional status and adverse prognosis. Among 732 elderly Framingham Study subjects (mean age 78 years, 67% women), who were free of prior myocardial infarction and CHF, serum IL-6, C-reactive protein (CRP), and spontaneous production of tumour necrosis factor (TNF)-a were obtained at baseline and then after 5 years. After adjustment for established risk factors, including the occurrence of myocardial infarction on follow-up, there was an increased risk of CHF per tertile increment in cytokine concentration (60% for TNF-a and 68% for serum IL-6, respectively). A serum CRP level greater than 5 mg/dl was associated with a 2.8-fold increased risk of CHF. Subjects with elevated levels of all three biomarkers (serum IL-6, TNF-a, and CRP), had a four-fold increased risk of CHF (95% CI 1.34-12.37). Thus, a single determination of serum inflammatory markers, particularly elevated IL-6, was associated with increased risk of CHF in people without prior myocardial infarction [47]. Other studies have also demonstrated that the highest levels of TNF-a are associated with the poorest functional status in CHF patients [48].

IL-1, IL-6, TNF-a (cachexin), interferon (IFN)-Y, leukaemia inhibitory factor (D-factor), and prostaglandin E2 have been associated with cancer cachexia. The possible transfer of these cytokines via the circulation has been demonstrated in non-tumour bearing rats, who developed cachexia after parabiotic anastomosis to sarcoma-bearing cachexia rats [49].

There is increasing evidence that cytokines can produce cognitive impairment [50, 51]. Cytokines, besides producing a direct effect on muscle function, may also impair functional status by altering central nervous system function. Cognitive impairment has been demonstrated to be associated with functional decline [52-56].

Cytokines are also related to a number of disease conditions, including cancer [57], end-stage renal disease [58], chronic pulmonary disease [59], CHF [60], rheumatoid arthritis [61], and AIDS [62]. These same conditions are frequently associated with a decline in functional status. Cytokines, especially IL-1, IL-6 and TNF-a, are potent causes of appetite suppression, weight loss, and hypoal-

buminaemia [63-65], and play a role in mortality, weight loss, and appetite suppression. Cytokines also decreased haemoglobin levels [66], which has been shown to be associated with disability [67].

Not all populations demonstrate a direct relationship between functional status and cytokine levels. In subjects on maintenance haemodialysis, the levels of inflammatory cytokines are uniformly high. No significant associations among inflammatory cytokines and physical activity, performance, or function has been shown in this population [68]. Whether functional status is directly related to the level of cytokines or independent of cytokine status in this population is unknown.

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