The innate immune system: friend and foe
Advancing age is associated with diminished immune function. This is true for adaptive immunity, which is mediated by T and B lymphocytes (1), and for some aspects of innate immunity, which include the activity of phagocytic cells such as macrophages (2). Although aspects of innate immunity may be compromised by age, aging is often associated with increases in systemic markers of inflammation. Such markers include plasma concentrations of tumor necrosis factor (TNF-) and interleukin 6 (IL-6) (3), which suggest an increased activity of the innate immune system later in life. Some argue that an increased activity of the innate immune system may be adaptive and may contribute to a long life (4). However, elevated markers of inflammation in the aged are associated with disability and death (5). This is not surprising because many diseases of aging have an inflammatory component that results from activation of the innate immune system. For example, cardiovascular disease involves chronic inflammation in the arterial wall that is mediated, in part, by macrophages activated by oxidized lipids (6, 7). Thus, innate immunity is our friend because it protects against pathogens, but it may also be our foe when it plays a role in chronic disease.
One of the principal goals of nutrition science in the early 21st century is to promote healthy aging. An important avenue toward this goal involves the evaluation of antiinflammatory dietary interventions. The explicit goal of these interventions is to diminish innate immune responses that contribute to chronic disease. The possible downside of such interventions is that they may also diminish host defenses against pathogenic organisms. Arguably, the intervention that has moved farthest down this avenue is the use of n–3 (–3) fatty acids to decrease the risk and severity of inflammatory conditions such as cardiovascular disease. This strategy is endorsed by the American Heart Association (8), which recommends that all adults eat fish rich in n–3 fatty acids such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). The American Heart Association further recommends that those persons at risk of cardiovascular disease consume from 1 to 3 g/d of EPA and DHA as supplements. One of the mechanisms presumed to be behind this reduction in risk is the competition of EPA (20:5n–3) with arachidonic acid (AA; 20:4n–6) as a substrate for the synthesis of oxylipids, such as prostaglandins and leukotrienes. The 4-series leukotrienes and the 2-series prostaglandins derived from AA are proinflammatory and mediate key events in the development of plaque (7). Thus, an important benefit of increasing the EPA intake is an increase in the EPA:AA ratio in monocyte membranes; when these cells extravasate into arterial lesions and become macrophages, they produce fewer proinflammatory oxylipids and thus contribute less to disease progression.
Even though n–3 supplements are widely accepted as beneficial, many questions remain to be answered. The study by Rees et al (9) in this issue of the Journal examines one of these questions: Does supplement use impair innate immunity? The study had several strengths. First, the authors used a placebo-controlled study design with multiple doses of an EPA-rich fish-oil concentrate. Although the doses used in the study by Rees et al (1.6, 3.3, and 5.0 g/d) did not cover the low end of the supplement range, the doses used were reasonable because lower doses were tested in many previous studies (10), and the principal focus of this study was the potential adverse effects, which are more likely at higher doses. Another strength of the study was that multiple endpoints were examined, including the expression of adhesion molecules on monocytes, phagocytic capacity and oxidative burst of activated neutrophils and monocytes independently, prostaglandin E production by mononuclear cells, and production of proinflammatory cytokines by mononuclear cells. A third important aspect was that the study examined both younger (18–42 y) and older (53–72 y) men. This is important because chronic disease prevention should start early in life.
What did the authors find? As expected, supplement use increased the EPA concentration and the EPA:AA ratio in plasma and mononuclear cell membranes. Interestingly, the increases were greater in the older than in the younger subjects. The authors attributed this difference between the age groups to a difference in fatty acid metabolism between the 2 groups, but, because dietary intake was not assessed, this conclusion is only speculative. Prostaglandin E2 production decreased as a function of the increasing EPA:AA ratio, as expected. IL-1, TNF-, and IL-6 concentrations did not change. Earlier studies (10) showed decreases in these cytokines, and the lack of effect in the present study may have been due to the relatively high content of -tocopherol in the supplements (32 mg/d) or to the use of a maximal rather than a submaximal stimulus for cytokine production. Monocyte phagocytic capacity and oxidative burst did not change. Neutrophil phagocytic capacity did not change, but the neutrophil oxidative burst decreased with increasing supplement doses in a dose-response fashion. Interestingly, this change was seen only in the older subjects. This finding suggests that the antibacterial activity of neutrophils may be impaired, at least at doses 1.6 g/d. Many studies, including others by Rees et al, examined similar endpoints, as discussed in a recent review (10). The findings of the current study by Rees et al generally agree with this earlier work. The lowest dose of EPA + DHA previously found to inhibit superoxide production by neutrophils was 2.2 g/d, whereas all studies that used supplements containing >4.7 g/d showed such inhibition.
We noted the strengths of the study, but the study also had limitations—as do all studies. For example, the subject group was limited to men. It is important to study both sexes, particularly because many aspects of immune function differ by sex. Another limitation was that the duration of the study (12 wk) was relatively short. Doctors and nutritionists recommend that n–3 fatty acid intakes be adjusted for life. It would be useful to know the long-term effects of these supplements.
What shall we conclude from this study with regard to the adverse effects of n–3 intakes on innate immunity? First, the n–3 intake that we are likely to achieve by eating fish does not appear to inhibit the measures of innate immunity examined here. Second, even though supplements taken at recommended amounts to decrease the risk of cardiovascular disease diminish the oxidative burst of neutrophils, the decrease is modest (<15%) and seems unlikely to significantly impair innate immunity.
In closing, it is important to remember that the innate immune system is designed to protect us against life-threatening infections, although it may also harm us as a mediator of chronic inflammatory diseases. In light of this harm, antiinflammatory dietary interventions do have a role to play in promoting healthy aging. However, the work of Rees et al (9) reminds us that we should always think about unintended consequences. Such antiinflammatory interventions should always be evaluated for risks as well as benefits. Everyone knows that it is folly to kill the goose that lays the golden eggs. It is also folly to kill the immune system that got us through childhood and middle age; we also need it to get us through a healthy old age.
REFERENCES
Franceschi C, Bonafe M, Valensin S. Human immunosenescence: the prevailing of innate immunity, the failing of clonotypic immunity, and the filling of immunological space. Vaccine 2000;18:1717-20.
Plowden J, Renshaw-Hoelscher M, Engleman C, Katz J, Sambhara S. Innate immunity in aging: impact on macrophage function. Aging Cell 2004;3:161-7.
Bruunsgaard H, Pedersen M, Pedersen BK. Aging and proinflammatory cytokines. Curr Opin Hematol 2001;8:131-6.
DeVeale B, Brummel T, Seroude L. Immunity and aging: the enemy within? Aging Cell 2004;3:195-208.
Kritchevsky SB, Cesari M, Pahor M. Inflammatory markers and cardiovascular health in older adults. Cardiovasc Res 2005;66:265-75.
Michelsen KS, Doherty TM, Shah PK, Arditi M. TLR signaling: an emerging bridge from innate immunity to atherogenesis. J Immunol 2004;173:5901-7.
Mehrabian M, Allayee H. 5-Lipoxygenase and atherosclerosis. Curr Opin Lipidol 2003;14:447-57.
Kris-Etherton PM, Harris WS, Appel LJ. Omega-3 fatty acids and cardiovascular disease: new recommendations from the American Heart Association. Arterioscler Thromb Vasc Biol 2003;23:151-2.
Rees D, Miles EA, Banerjee T, et al. Dose-related effects of eicosapentaenoic acid on innate immune function in healthy humans: a comparison of young and older men. Am J Clin Nutr 2006;83:331-42.
Kelley DS, Hubbard NE, Erickson KE. Regulation of human immune and inflammatory responses by dietary fatty acids. Adv Food Nutr Res 2005;50:101-38., http://www.100md.com(Charles B Stephensen1 and)
One of the principal goals of nutrition science in the early 21st century is to promote healthy aging. An important avenue toward this goal involves the evaluation of antiinflammatory dietary interventions. The explicit goal of these interventions is to diminish innate immune responses that contribute to chronic disease. The possible downside of such interventions is that they may also diminish host defenses against pathogenic organisms. Arguably, the intervention that has moved farthest down this avenue is the use of n–3 (–3) fatty acids to decrease the risk and severity of inflammatory conditions such as cardiovascular disease. This strategy is endorsed by the American Heart Association (8), which recommends that all adults eat fish rich in n–3 fatty acids such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). The American Heart Association further recommends that those persons at risk of cardiovascular disease consume from 1 to 3 g/d of EPA and DHA as supplements. One of the mechanisms presumed to be behind this reduction in risk is the competition of EPA (20:5n–3) with arachidonic acid (AA; 20:4n–6) as a substrate for the synthesis of oxylipids, such as prostaglandins and leukotrienes. The 4-series leukotrienes and the 2-series prostaglandins derived from AA are proinflammatory and mediate key events in the development of plaque (7). Thus, an important benefit of increasing the EPA intake is an increase in the EPA:AA ratio in monocyte membranes; when these cells extravasate into arterial lesions and become macrophages, they produce fewer proinflammatory oxylipids and thus contribute less to disease progression.
Even though n–3 supplements are widely accepted as beneficial, many questions remain to be answered. The study by Rees et al (9) in this issue of the Journal examines one of these questions: Does supplement use impair innate immunity? The study had several strengths. First, the authors used a placebo-controlled study design with multiple doses of an EPA-rich fish-oil concentrate. Although the doses used in the study by Rees et al (1.6, 3.3, and 5.0 g/d) did not cover the low end of the supplement range, the doses used were reasonable because lower doses were tested in many previous studies (10), and the principal focus of this study was the potential adverse effects, which are more likely at higher doses. Another strength of the study was that multiple endpoints were examined, including the expression of adhesion molecules on monocytes, phagocytic capacity and oxidative burst of activated neutrophils and monocytes independently, prostaglandin E production by mononuclear cells, and production of proinflammatory cytokines by mononuclear cells. A third important aspect was that the study examined both younger (18–42 y) and older (53–72 y) men. This is important because chronic disease prevention should start early in life.
What did the authors find? As expected, supplement use increased the EPA concentration and the EPA:AA ratio in plasma and mononuclear cell membranes. Interestingly, the increases were greater in the older than in the younger subjects. The authors attributed this difference between the age groups to a difference in fatty acid metabolism between the 2 groups, but, because dietary intake was not assessed, this conclusion is only speculative. Prostaglandin E2 production decreased as a function of the increasing EPA:AA ratio, as expected. IL-1, TNF-, and IL-6 concentrations did not change. Earlier studies (10) showed decreases in these cytokines, and the lack of effect in the present study may have been due to the relatively high content of -tocopherol in the supplements (32 mg/d) or to the use of a maximal rather than a submaximal stimulus for cytokine production. Monocyte phagocytic capacity and oxidative burst did not change. Neutrophil phagocytic capacity did not change, but the neutrophil oxidative burst decreased with increasing supplement doses in a dose-response fashion. Interestingly, this change was seen only in the older subjects. This finding suggests that the antibacterial activity of neutrophils may be impaired, at least at doses 1.6 g/d. Many studies, including others by Rees et al, examined similar endpoints, as discussed in a recent review (10). The findings of the current study by Rees et al generally agree with this earlier work. The lowest dose of EPA + DHA previously found to inhibit superoxide production by neutrophils was 2.2 g/d, whereas all studies that used supplements containing >4.7 g/d showed such inhibition.
We noted the strengths of the study, but the study also had limitations—as do all studies. For example, the subject group was limited to men. It is important to study both sexes, particularly because many aspects of immune function differ by sex. Another limitation was that the duration of the study (12 wk) was relatively short. Doctors and nutritionists recommend that n–3 fatty acid intakes be adjusted for life. It would be useful to know the long-term effects of these supplements.
What shall we conclude from this study with regard to the adverse effects of n–3 intakes on innate immunity? First, the n–3 intake that we are likely to achieve by eating fish does not appear to inhibit the measures of innate immunity examined here. Second, even though supplements taken at recommended amounts to decrease the risk of cardiovascular disease diminish the oxidative burst of neutrophils, the decrease is modest (<15%) and seems unlikely to significantly impair innate immunity.
In closing, it is important to remember that the innate immune system is designed to protect us against life-threatening infections, although it may also harm us as a mediator of chronic inflammatory diseases. In light of this harm, antiinflammatory dietary interventions do have a role to play in promoting healthy aging. However, the work of Rees et al (9) reminds us that we should always think about unintended consequences. Such antiinflammatory interventions should always be evaluated for risks as well as benefits. Everyone knows that it is folly to kill the goose that lays the golden eggs. It is also folly to kill the immune system that got us through childhood and middle age; we also need it to get us through a healthy old age.
REFERENCES
Franceschi C, Bonafe M, Valensin S. Human immunosenescence: the prevailing of innate immunity, the failing of clonotypic immunity, and the filling of immunological space. Vaccine 2000;18:1717-20.
Plowden J, Renshaw-Hoelscher M, Engleman C, Katz J, Sambhara S. Innate immunity in aging: impact on macrophage function. Aging Cell 2004;3:161-7.
Bruunsgaard H, Pedersen M, Pedersen BK. Aging and proinflammatory cytokines. Curr Opin Hematol 2001;8:131-6.
DeVeale B, Brummel T, Seroude L. Immunity and aging: the enemy within? Aging Cell 2004;3:195-208.
Kritchevsky SB, Cesari M, Pahor M. Inflammatory markers and cardiovascular health in older adults. Cardiovasc Res 2005;66:265-75.
Michelsen KS, Doherty TM, Shah PK, Arditi M. TLR signaling: an emerging bridge from innate immunity to atherogenesis. J Immunol 2004;173:5901-7.
Mehrabian M, Allayee H. 5-Lipoxygenase and atherosclerosis. Curr Opin Lipidol 2003;14:447-57.
Kris-Etherton PM, Harris WS, Appel LJ. Omega-3 fatty acids and cardiovascular disease: new recommendations from the American Heart Association. Arterioscler Thromb Vasc Biol 2003;23:151-2.
Rees D, Miles EA, Banerjee T, et al. Dose-related effects of eicosapentaenoic acid on innate immune function in healthy humans: a comparison of young and older men. Am J Clin Nutr 2006;83:331-42.
Kelley DS, Hubbard NE, Erickson KE. Regulation of human immune and inflammatory responses by dietary fatty acids. Adv Food Nutr Res 2005;50:101-38., http://www.100md.com(Charles B Stephensen1 and)