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• W1967039991 abstract "Upon physiological stress, families of stress response genes are activated as natural defense mechanisms. Here, we show that induction of specific inflammatory genes is significantly dysregulated and altered in the heart of aged (24–26-month-old)versus young (4-month-old) mice experimentally challenged with a bacterial endotoxin, lipopolysaccharide (LPS, 1.5 mg/kg of body mass). Whereas the LPS-mediated induction of cardiac mRNA for tumor necrosis factor α or inducible nitric-oxide synthase showed no age-associated differences, the induction of interleukin-1β (IL-1β) and intracellular adhesion molecule-1 was modestly extended with aging, and the induction of IL-6 was significantly prolonged with aging. This age-associated phenomenon occurred gradually from 4 to 17 months of age and became more evident after 23 months of age. The age-associated augmentation of the cardiac IL-6 induction was also dramatic at the protein level. Immunohistochemically, the LPS-induced cardiac IL-6 was localized mainly in the microvascular walls. Aged but not young mice showed a high mortality rate during these experiments. These results demonstrate that endotoxin-mediated induction of specific inflammatory genes in cardiovascular tissues is altered with aging, which may be causally related to the increased susceptibility of aged animals to endotoxic stress. Upon physiological stress, families of stress response genes are activated as natural defense mechanisms. Here, we show that induction of specific inflammatory genes is significantly dysregulated and altered in the heart of aged (24–26-month-old)versus young (4-month-old) mice experimentally challenged with a bacterial endotoxin, lipopolysaccharide (LPS, 1.5 mg/kg of body mass). Whereas the LPS-mediated induction of cardiac mRNA for tumor necrosis factor α or inducible nitric-oxide synthase showed no age-associated differences, the induction of interleukin-1β (IL-1β) and intracellular adhesion molecule-1 was modestly extended with aging, and the induction of IL-6 was significantly prolonged with aging. This age-associated phenomenon occurred gradually from 4 to 17 months of age and became more evident after 23 months of age. The age-associated augmentation of the cardiac IL-6 induction was also dramatic at the protein level. Immunohistochemically, the LPS-induced cardiac IL-6 was localized mainly in the microvascular walls. Aged but not young mice showed a high mortality rate during these experiments. These results demonstrate that endotoxin-mediated induction of specific inflammatory genes in cardiovascular tissues is altered with aging, which may be causally related to the increased susceptibility of aged animals to endotoxic stress. lipopolysaccharide tumor necrosis factor α interleukin inducible nitric-oxide synthase intracellular adhesion molecule-1 Bacterial infection triggers cascades of inflammatory responses, which involve activation of various inflammatory mediators including cytokines, growth factors, and cell adhesion molecules. Although these inflammatory mediators act primarily for the host defense, they also cause pathophysiological conditions characteristic of sepsis. Upon infection with Gram-negative bacteria, released endotoxin (e.g. lipopolysaccharide, LPS)1 stimulates monocytes/macrophages to produce such initial proinflammatory cytokines as tumor necrosis factor α (TNFα) and interleukin 1β (IL-1β). These two in turn elicit a subsequent release of secondary inflammatory mediators, including inducible nitric-oxide synthase (iNOS), intracellular adhesion molecule-1 (ICAM-1), and IL-6 (1Lamy M. Deby-Dupont G. Intensive Care Med. 1995; 21 Suppl. 2: 250-257Crossref Scopus (30) Google Scholar). TNFα is known to function synergistically with IL-1β to cause myocardial depression during acute septic shock (2Kumar A. Thota V. Dee L. Olson J. Uretz E. Parrillo J.E. J. Exp. Med. 1996; 183: 949-958Crossref PubMed Scopus (626) Google Scholar). Induction of iNOS and subsequent production of nitric oxide are known to be important mediators for systemic vasodilatation and hypotension during septic shock (3Grocott-Mason R.M. Shah A.M. Intensive Care Med. 1998; 24: 286-295Crossref PubMed Scopus (81) Google Scholar). ICAM-1 promotes neutrophil-myocardial or neutrophil-vascular endothelial cell adhesion, which causes cardiovascular tissue injury due to the cytotoxic activity of neutrophils (4Smith C.W. Entman M.L. Lane C.L. Beaudet A.L. Ty T.I. Youker K. Hawkins H.K. Anderson D.C. J. Clin. Invest. 1991; 88: 1216-1223Crossref PubMed Scopus (147) Google Scholar, 5Youker K. Smith C.W. Anderson D.C. Miller D. Michael L.H. Rossen R.D. Entman M.L. J. Clin. Invest. 1992; 89: 602-609Crossref PubMed Scopus (169) Google Scholar, 6Mantovani A. Bussolino F. Dejana E. FASEB J. 1992; 6: 2591-2599Crossref PubMed Scopus (628) Google Scholar). IL-6, a multifunctional cytokine produced by a variety of cells, is known to play important roles in immunological/inflammatory responses, hematopoiesis (7Akira S. Kishimoto T. Immunol. Rev. 1992; 127: 25-50Crossref PubMed Scopus (471) Google Scholar), and synthesis of liver acute phase proteins (8Castell J.V. Gomez-Lechon M.J. David M. Andus T. Geiger T. Trullenque R. Fabra R. Heinrich P.C. FEBS Lett. 1989; 242: 237-239Crossref PubMed Scopus (736) Google Scholar). High levels of IL-6 appear to have deleterious effects during systemic inflammation, because a reduced endotoxic mortality rate was observed in mice after treatment with anti-IL6 antibodies (9Starnes Jr., H.F. Pearce M.K. Tewari A. Yim J.H. Zou J.C. Abrams J.S. J. Immunol. 1990; 145: 4185-4191PubMed Google Scholar). IL-6 is also known to exert a negative inotropic effect on myocardial tissues (10Finkel M.S. Oddis C.V. Jacob T.D. Watkins S.C. Hattler B.G. Simmons R.L. Science. 1992; 257: 387-389Crossref PubMed Scopus (1494) Google Scholar,11Finkel M.S. Hoffman R.A. Shen L. Oddis C.V. Simmons R.L. Hattler B.G. Am. J. Cardiol. 1993; 71: 1231-1232Abstract Full Text PDF PubMed Scopus (134) Google Scholar). We have recently demonstrated that intraperitoneal injection of young mice with LPS results in a rapid induction of mRNA for IL-1β and TNFα, followed by a strong induction of IL-6 and ICAM-1 in the heart. The IL-6 induction in the heart was more intense than in any other tissue examined, including brain, lung, liver, kidney, spleen, and skeletal muscle (12Saito H. Patterson C. Hu Z. Runge M.S. Tipnis U. Sinha M. Papaconstantinou J. Am. J. Physiol. 2000; 279: H2241-H2248PubMed Google Scholar). Aging is characterized by an altered immune function and stress response (13Papaconstantinou J. Reisner P.D. Liu L. Kunninger D. Schneider E.L. Rowe J.W. Handbook of the Biology of Aging. 4th Ed. Academic Press, San Diego, CA1996: 150-183Google Scholar, 14Miller R.A. Schneider E.L. Rowe J.W. Handbook of the Biology of Aging. 4th Ed. Academic Press, San Diego, CA1996: 355-392Google Scholar). Cardiovascular function during stress also declines with aging (15Lakatta E.G. Schneider E.L. Rowe J.W. Handbook of the Biology of Aging. 3rd Ed. Academic Press, San Diego, CA1990: 181-218Google Scholar). Thus, we hypothesized that induction of stress response genes in the heart may be altered with aging. In the present study, we show that LPS-induced expression of specific genes, including those for IL-1β, ICAM-1, and IL-6 in particular, is significantly prolonged and augmented in the hearts of aged mice compared with young mice. We also show that the endotoxin-induced cardiac IL-6 is mainly localized to microvascular walls in the heart. Male C57BL/6, BALB/c, and CB6F1 mice were obtained from colonies of the National Institute on Aging through Charles River Laboratories (Wilmington, MA). The newly arrived animals were kept at least 10 days in a 12/12 h light/dark cycle and fed a standard chow diet ad libitum before experiments. Mice were injected intraperitoneally with LPS (derived from Pseudomonas aeruginosa, Sigma) at a dose of 1.5 µg/g of body mass. In some experiments, in which young and aged mice did not show a significant difference in their body masses, all mice were injected with the same amount of LPS (50 µg, equivalent to ∼1.5 µg/g of body mass). After injection, animals, together with control non-injected mice, were sacrificed by cervical dislocation at the indicated time points, and tissues were quickly dissected. At the same time, other major organs including brain, lung, liver, kidney, spleen, and intestines were harvested and examined. Mice that exhibited any signs of abnormality, such as injury and tumor, were eliminated from the experiments. These procedures were approved by the University of Texas Medical Branch Institutional Animal Care and Use Committee. Total RNA was isolated using guanidine/phenol, and Northern blot hybridization was performed as described previously (12Saito H. Patterson C. Hu Z. Runge M.S. Tipnis U. Sinha M. Papaconstantinou J. Am. J. Physiol. 2000; 279: H2241-H2248PubMed Google Scholar). Slot blot hybridization analysis for the IL-6 mRNA was performed using a Manifold II slot blot apparatus (Schleicher & Schuell) with the same hybridization condition as Northern blot analysis. Cytoplasmic proteins were extracted from mouse hearts as described previously (12Saito H. Patterson C. Hu Z. Runge M.S. Tipnis U. Sinha M. Papaconstantinou J. Am. J. Physiol. 2000; 279: H2241-H2248PubMed Google Scholar). The cytokine concentrations were determined by enzyme-linked immunosorbent assays using a commercial kit specific for mouse IL-1β, TNFα, and IL-6 (Endogen, Inc., Woburn, MA). The detection limits of this kit were 3, 10, and 7 pg/ml, respectively. Cryo-sections of mouse hearts were incubated overnight at 4 °C with polyclonal rabbit anti-rat IL-6 antibody SC-1267 (Santa Cruz Biotechnology, Santa Cruz, CA). After serial washings with phosphate-buffered saline, the slides were incubated with biotinylated secondary antibody for 45 min at room temperature. The sections were developed with ABC reagent (ABC kit, Vector Laboratories, Burlingame, CA) for 45 min. After incubation in Fast Red (Sigma, F-4648) containing 1 mm levamisole, the slides were mounted for light microscopy (12Saito H. Patterson C. Hu Z. Runge M.S. Tipnis U. Sinha M. Papaconstantinou J. Am. J. Physiol. 2000; 279: H2241-H2248PubMed Google Scholar). To determine whether cardiovascular gene expression during the inflammatory response is altered by aging, we compared the endotoxin-mediated induction of mRNAs for several inflammatory genes in the hearts of young (4-month-old) versus aged (24-month-old) C57BL/6 mice. Mice were injected with 50µg of LPS, and sacrificed at 1, 3, 6, 12, and 24 h thereafter together with control non-injected mice (four mice per time point). During these experiments, we confirmed the previously reported higher mortality rate in aged mice by endotoxic stress (16Tateda K. Matsumoto T. Miyazaki S. Yamaguchi K. Infect. Immun. 1996; 64: 769-774Crossref PubMed Google Scholar,17Tanabe O. Akira S. Kamiya T. Wong G.G. Hirano T. Kishimoto T. J. Immunol. 1988; 141: 3875-3881PubMed Google Scholar). Approximately 10% of aged mice died within 24 h after LPS injection, whereas no young mice died during the same time period. We analyzed the RNA from the hearts by Northern blot hybridization and examined the induction of inflammatory genes, including IL-1β, TNFα, IL-6, ICAM-1, and iNOS. As shown in Fig.1, the IL-1β and TNFα mRNA levels peaked at 1 h, the ICAM-1 and IL-6 mRNA levels peaked at 3 h, and the iNOS mRNA levels peaked at 6 h post-injection in both young and aged mice. The kinetics confirmed that the two early inflammatory genes, IL-1β and TNFα, are induced before the secondary inflammatory mediator genes, ICAM-1, IL-6, and iNOS, in the heart. Whereas the TNFα and iNOS mRNA levels did not show significant age-associated differences, the induced IL-6 mRNA levels after the peak time point were significantly higher in aged mice than in young mice. There was also an age-associated elevation in IL-1β and ICAM-1 mRNA levels at certain time points, although not to the same extent as in IL-6. These results demonstrate that aging alters the induction patterns of specific inflammatory genes in the heart during endotoxic stress. The high levels of IL-6 mRNA observed in the aged mice may be caused by a prolonged induction of the gene in all aged mice or possibly by the inclusion of one aged mouse or a few aged mice that were induced to produce exceptionally high levels of IL-6 mRNA. To distinguish these possibilities, we measured the IL-6 mRNA level in each individual young or aged mouse throughout the time course. As shown in Fig. 1, B and C, induction of IL-6 mRNA in young hearts consistently occurred at 3 h after LPS injection, and the mRNA levels came back to near the undetectable basal level by 6 h. The standard deviations for the young mice were small at all time points, suggesting that induction of the IL-6 gene in the heart is tightly regulated in young animals. On the other hand, the IL-6 mRNA induction varied substantially among individual aged mice, suggesting that induction of the IL-6 gene is dysregulated in aged hearts. At 3 h after LPS injection, the IL-6 mRNA was induced very strongly in one aged mouse and was not induced at all in two others, suggesting that the IL-6 induction in response to LPS can be augmented or delayed in some aged mice. From 6 to 12 h after LPS injection, all the aged mice showed high levels of induced IL-6 mRNA, equivalent to the average peak level in young mice. Even at 24 h post-injection, high levels of the IL-6 mRNA were still detected in some of the aged mice. Because persistently high levels of IL-6 mRNA were commonly seen in aged mice, we concluded that induction of the cardiac IL-6 mRNA in response to endotoxic shock is prolonged in aged animals. To determine whether the age-associated differential induction of IL-6 mRNA is specific to the C57BL/6 mouse or is common among other strains, we conducted similar experiments using three different mouse strains, C57BL/6, BALB/c, and their hybrid CB6. For this experiment, we compared the induced IL-6 mRNA levels in the hearts of young (4–7-month-old)versus aged (24–28-month-old) mice 6 h after LPS injection (n = 4). We chose this time point because it was a time where IL-6 mRNA levels differ significantly in young and aged C57BL/6 mice. As demonstrated in Fig.2, the LPS-induced IL-6 mRNA levels were significantly higher than those in young hearts, not only in C57BL/6 mice but also in BALB/c and CB6 mice. These results suggest that the age-associated extended induction of the IL-6 gene in response to LPS is not mouse strain-specific. We sought to determine at what age the endotoxin-mediated induction of the cardiac IL-6 changes, i.e. whether this is a gradual change or one that occurs at a specific age. We compared the cardiac IL-6 mRNA levels at 6 h post-LPS injection among four different age groups: 4-, 10-, 16–17-, and 23–27-month old (n = 6–8 per group). As shown in Fig.3, the age-associated overexpression of the IL-6 gene occurred in some mice by the age of 10 months, became significant at age 16–17 months, and was even more dramatic at 23 months and later. Statistically significant differences were found between the 4- and 23–27-month-old groups (p < 0.001) and also between the 4- and 16–17-month-old groups (p< 0.01) but not between the 4- and 10-month-old groups (p > 0.3). Thus, we conclude that the age-associated elevation of IL-6 gene induction is not evident until at least 10 months of age, but it occurs by 16 months of age and becomes greater with increasing age. In these experiments we used enzyme-linked immunosorbent assay to compare the cytokine protein levels in the hearts of young versus aged mice that were injected with 50 µg of LPS and sacrificed at 1, 3, 6, 12, and 24 h thereafter, together with control non-injected mice (three to six mice per time point). The IL-6 levels at 0 and 1 h were ∼20 pg/mg of protein or less in both young and aged mice. In young mice, a rapid increase and subsequent decline in the cardiac IL-6 protein levels were seen at 3 and 6 h, respectively, demonstrating that the induction of IL-6 protein synthesis follows the pattern of induced mRNA levels (see Figs. 1 A and 4). The average IL-6 protein levels in the aged hearts were 7.5–35-fold higher than those in the young hearts from 3 to 24 h after LPS injection. All the aged mice showed higher cardiac IL-6 levels than the young mice from 3 to 12 h after LPS injection. Even 24 h after LPS injection, one of the aged mice still showed a higher IL-6 level than the average peak IL-6 level (at 3 h) in young mice. Using the same protein samples, we also measured IL-1β and TNFα levels in youngversus aged mice hearts. IL-1β induction was modestly elevated in aged mice compared with young mice (2.2-fold elevation at the peak level; Fig. 4 B), but TNFα induction did not show any difference in young versusaged mice (data not shown). The data for these two proteins also agree with the mRNA data (Fig.1) that IL-1β showed moderate age-associated elevation whereas TNFα induction was not affected by aging. These results demonstrate that, during endotoxic stress, the age-associated overexpression of specific inflammatory cytokines occurs not only at the mRNA level but also at the protein level. We performed immunohistochemical analyses to localize IL-6 in the young and aged mouse hearts during endotoxic stress. Young (4-month-old) and aged (26-month-old) C57BL/6 mice were injected with LPS (1.5 µg/g of body mass) and sacrificed 6 h later, and frozen heart sections were prepared. Immunohistochemical analyses using anti-IL-6 antibody detected IL-6 mostly in nonmyocardial cells, particularly in the microvascular walls of hearts from both young and aged mice, suggesting that IL-6 is expressed mostly in vascular endothelial cells (Fig.5, A and B). IL-6 was also detected in relatively large vessels in both young and aged mice (Fig. 5 C) and in a small number of myocardial cells only in aged mice (Fig. 5 B). In the present study, we clearly demonstrated a significantly elevated and prolonged induction of IL-6 in aged mouse hearts during endotoxic stress. Induction of the IL-1β and ICAM-1 genes was also elevated or extended in the aged mice, although the extent was not as dramatic as for IL-6. IL-1β is an important inducer of both IL-6 and ICAM-1 (4Smith C.W. Entman M.L. Lane C.L. Beaudet A.L. Ty T.I. Youker K. Hawkins H.K. Anderson D.C. J. Clin. Invest. 1991; 88: 1216-1223Crossref PubMed Scopus (147) Google Scholar, 12Saito H. Patterson C. Hu Z. Runge M.S. Tipnis U. Sinha M. Papaconstantinou J. Am. J. Physiol. 2000; 279: H2241-H2248PubMed Google Scholar); so the elevated IL-1β expression may be responsible for the prolonged induction of the ICAM-1 gene in aged mice. However, the moderate elevation of IL-1β expression alone cannot explain the dramatic overexpression of IL-6 in the aged mice. Because the LPS-mediated induction of a subset of inflammatory genes was altered in aged mice, we propose that the augmented induction of these genes probably is not caused by a decreased rate of clearance of endotoxin from aged animals. The augmented induction of the IL-6 gene may be due to an increased transcriptional rate for the gene and/or a decreased rate of its mRNA degradation in aged tissues. The regulatory region of the IL-6 gene contains putative binding sites for such stress-activated transcription factors as nuclear factor κB and nuclear factor/IL-6 (NF/IL6) (17Tanabe O. Akira S. Kamiya T. Wong G.G. Hirano T. Kishimoto T. J. Immunol. 1988; 141: 3875-3881PubMed Google Scholar) whose DNA binding activities increase with aging in mouse heart and liver, respectively (18Helenius M. Hanninen M. Lehtinen S.K. Salminen A. J. Mol. Cell. Cardiol. 1996; 28: 487-498Abstract Full Text PDF PubMed Scopus (182) Google Scholar, 19Hsieh C.C. Xiong W. Xie Q. Rabek J.P. Scott S.G. An M.R. Reisner P.D. Kuninger D.T. Papaconstantinou J. Mol. Biol. Cell. 1998; 9: 1479-1494Crossref PubMed Scopus (58) Google Scholar). Such an age-related increase in the activation of transcription factors may enhance the transcriptional rate of the IL-6 gene and increase pool levels for its mRNA. On the other hand, there have been studies suggesting that the expression of several inflammatory genes is regulated by mRNA stability and that the stabilization is altered by aging and inflammatory signals (20Kumar S. Millis A.J. Baglioni C. Proc. Natl. Acad. Sci. U. S. A. 1992; 89: 4683-4687Crossref PubMed Scopus (124) Google Scholar, 21Akashi M. Loussararian A.H. Adelman D.C. Saito M. Koeffler H.P. J. Clin. Invest. 1990; 85: 121-129Crossref PubMed Scopus (67) Google Scholar). It is yet to be determined whether stability of the IL-6 mRNA in the cardiovascular tissues increases with age. Our results demonstrated that the age-associated overexpression of IL-6 in the heart occurs more dramatically at the protein level than at the mRNA level. The age-associated increases in average peak levels (3 h after LPS injection) were ∼1.5- and 10-fold at the mRNA and protein levels, respectively (Figs. 1 C and 4). The difference in the magnitude of increase between the mRNA and protein levels raises the possibility that either the translational rate or protein stability of IL-6 is increased in the aged mouse heart. Whereas the IL-6 mRNA is solely derived from cardiac expression, the IL-6 protein may be produced in other tissues and reach the heart via the circulation. Indeed, the activity of plasma IL-6 after injection with LPS was reportedly higher in aged rats than in young rats (22Foster K.D. Conn C.A. Kluger M.J. Am. J. Physiol. 1992; 262: R211-R215PubMed Google Scholar). Thus, although we have recently shown that the heart induces the highest level of IL-6 mRNA among all major tissues in young mice during endotoxic stress (12Saito H. Patterson C. Hu Z. Runge M.S. Tipnis U. Sinha M. Papaconstantinou J. Am. J. Physiol. 2000; 279: H2241-H2248PubMed Google Scholar), extra-cardiac tissues may also show profound age-associated overexpression of IL-6 as well. Our previous study using in situ hybridization andin vitro cell cultures demonstrated that cardiac IL-6 is expressed mainly by nonmyocardial cells via IL-1β action during endotoxic stress. In that study, we could not identify which nonmyocardial cells (i.e. fibroblasts, macrophages, vascular endothelial cells, or smooth muscle cells) express IL-6 (12Saito H. Patterson C. Hu Z. Runge M.S. Tipnis U. Sinha M. Papaconstantinou J. Am. J. Physiol. 2000; 279: H2241-H2248PubMed Google Scholar). In the present study, we found that cardiac IL-6 was mostly localized to microvascular walls, suggesting that microvascular endothelial cells are the major cell source of IL-6 produced during endotoxic stress. It has been demonstrated that cultured human endothelial cells express IL-6 strongly in response to IL-1β (23Sironi M. Breviario F. Proserpio P. Biondi A. Vecchi A. Van Damme J. Dejana E. Mantovani A. J. Immunol. 1989; 142: 549-553PubMed Google Scholar). Because IL-6 was also identified in relatively large vascular tissues, vascular smooth muscle cells may also express IL-6. According to previous in vitrostudies, macrophage cultures from the elderly produced less IL-6 than those from young subjects in response to LPS treatment (24Delpedro A.D. Barjavel M.J. Mamdouh Z. Faure S. Bakouche O. J. Interferon Cytokine Res. 1998; 18: 429-437Crossref PubMed Scopus (57) Google Scholar), whereas whole aorta cultures from aged rats produced more IL-6 than those from young rats after LPS treatment (25Belmin J. Bernard C. Corman B. Merval R. Esposito B. Tedgui A. Am. J. Physiol. 1995; 268: H2288-H2293PubMed Google Scholar). Therefore, vascular endothelial and smooth muscle cells are probably the major cells that overproduce IL-6 in the aged heart during endotoxic stress. Interestingly, IL-6 expression was detected in a small population of myocardial cells from LPS-treated aged, but not young, mice. This myocardial cell-derived IL-6 in aged mouse hearts may be attributed at least partly to the age-associated overproduction of cardiac IL-6. Because myocardial cells reportedly express IL-6 in vitro under hypoxic conditions (26Yamauchi-Takihara K. Ihara Y. Ogata A. Yoshizaki K. Azuma J. Kishimoto T. Circulation. 1995; 91: 1520-1524Crossref PubMed Scopus (265) Google Scholar), the IL-6 detected in myocardium of aged mice may be an indication of tissue ischemia during endotoxic shock. The role of IL-6 during systemic inflammation is complex. An early study demonstrated a reduced LPS-induced mortality rate in mice treated with anti-IL-6 antibodies, clearly suggesting that a high level of IL-6 is harmful during endotoxic shock (9Starnes Jr., H.F. Pearce M.K. Tewari A. Yim J.H. Zou J.C. Abrams J.S. J. Immunol. 1990; 145: 4185-4191PubMed Google Scholar). However, a more recent study showed a somewhat elevated LPS-induced mortality rate in IL-6 (−/−) knockout mice, suggesting that IL-6 may also have a beneficial role during endotoxic shock (27Xing Z. Gauldie J. Cox G. Baumann H. Jordana M. Lei X.F. Achong M.K. J. Clin. Invest. 1998; 101: 311-320Crossref PubMed Scopus (1192) Google Scholar). Indeed, as we have recently shown, IL-6 may have a self-regulatory function to suppress its own inducers (TNFα and IL-1β) in the heart during endotoxic stress (12Saito H. Patterson C. Hu Z. Runge M.S. Tipnis U. Sinha M. Papaconstantinou J. Am. J. Physiol. 2000; 279: H2241-H2248PubMed Google Scholar). IL-6 is a multifunctional cytokine and is often considered “a double-edged sword.” Upon physiological stress such as infection, an appropriate (and probably beneficial) amount of IL-6 is rapidly produced and presumably functions to protect tissues. As seen in Fig. 1, such induction is tightly regulated and does not last long in healthy young animals. On the other hand, uncontrolled overexpression of IL-6 is obviously harmful, because various transgenic mouse models overexpressing IL-6 develop various pathologies, including plasmacytosis (28Suematsu S. Matsuda T. Aozasa K. Akira S. Nakano N. Ohno S. Miyazaki J. Yamamura K. Hirano T. Kishimoto T. Proc. Natl. Acad. Sci. U. S. A. 1989; 86: 7547-7551Crossref PubMed Scopus (544) Google Scholar), adrenal hyperplasia (29Raber J. O'Shea R.D. Bloom F.E. Campbell I.L. J. Neurosci. 1997; 17: 9473-9480Crossref PubMed Google Scholar), cardiac hypertrophy (30Hirota H. Yoshida K. Kishimoto T. Taga T. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 4862-4866Crossref PubMed Scopus (450) Google Scholar), muscle atrophy (31Fujita J. Tsujinaka T. Ebisui C. Yano M. Shiozaki H. Katsume A. Ohsugi Y. Monden M. Eur. Surg. Res. 1996; 28: 361-366Crossref PubMed Scopus (30) Google Scholar), and growth retardation (32De Benedetti F. Alonzi T. Moretta A. Lazzaro D. Costa P. Poli V. Martini A. Ciliberto G. Fattori E. J. Clin. Invest. 1997; 99: 643-650Crossref PubMed Scopus (424) Google Scholar); this variety possibly results from the different tissues and levels of overexpression and the tissue distribution pattern of the IL-6 receptor. ICAM-1 promotes neutrophil-myocyte adhesion (5Youker K. Smith C.W. Anderson D.C. Miller D. Michael L.H. Rossen R.D. Entman M.L. J. Clin. Invest. 1992; 89: 602-609Crossref PubMed Scopus (169) Google Scholar), and IL-6 stimulates neutrophils to produce hydrogen peroxide (33Yuan L. Inoue S. Saito Y. Nakajima O. Exp. Cell Res. 1993; 209: 375-381Crossref PubMed Scopus (43) Google Scholar). Thus, overproduction of ICAM-1 and IL-6 in aged tissues during inflammation may cause elevated activation of neutrophils and resulting oxidative stress, which may lead to cardiovascular cell injury. In our study, mice were treated with a single LPS injection. However, in clinical septic conditions during infection, LPS is released continuously; so the duration of overexpression of these genes and resulting effects in aged animals may be far greater than that observed in our experimental model. The elderly show a significantly elevated mortality rate during septic shock after bacterial infection. Although the precise mechanisms for this increase in susceptibility to sepsis are largely unknown, mortality in elderly septic patients often depends on the physiological reserve and stress tolerance of the cardiovascular and pulmonary systems (34Stengle J. Dries D. Crit. Care Nurs. Clin. North Am. 1994; 6: 421-427Abstract Full Text PDF PubMed Google Scholar, 35Streat S.J. Plank L.D. Hill G.L. World J. Surg. 2000; 24: 655-663Crossref PubMed Scopus (22) Google Scholar). During sepsis, cascades of inflammatory response mediate various cardiovascular dysfunctions, including vascular endothelial cell damage, vascular permeabilization, vasodilatation, hypotension, and myocardial depression (36Baldwin K.M. Davey S.S. Morris S.E. Burger M. McCance K.L. Huether S.E. Pathophysiology: The Biologic Basis for Disease in Adults and Children. Mosby, Inc., St. Louis, MO1998: 1570-1601Google Scholar). Persistently high levels of serum IL-6 reportedly predict high mortality in septic patients (1Lamy M. Deby-Dupont G. Intensive Care Med. 1995; 21 Suppl. 2: 250-257Crossref Scopus (30) Google Scholar,37Thijs L.G. Hack C.E. Intensive Care Med. 1995; 21 Suppl. 2: 258-263Crossref Scopus (169) Google Scholar, 38Damas P. Ledoux D. Nys M. Vrindts Y. De Groote D. Franchimont P. Lamy M. Ann. Surg. 1992; 215: 356-362Crossref PubMed Scopus (691) Google Scholar, 39Simpson A.J. Smith M.D. Weverling G.J. Suputtamongkol Y. Angus B.J. Chaowagul W. White N.J. van Deventer S.J. Prins J.M. J. Infect. Dis. 2000; 181: 621-625Crossref PubMed Scopus (90) Google Scholar). Therefore, augmented induction of IL-1β, IL-6, and ICAM-1 in aged mouse hearts may be causally associated with the high mortality rate of aged mice during endotoxic stress. Endotoxin-mediated induction of TNFα and nitric oxide in plasma was reportedly increased modestly by aging (2-fold and 26%, respectively), and pretreatment with anti-TNFα antibody reduced LPS mortality rate in both young and aged mice, suggesting that TNFα has an important role in LPS mortality (40Chorinchath B.B. Kong L.Y. Mao L. McCallum R.E. J. Immunol. 1996; 156: 1525-1530PubMed Google Scholar). However, because LPS-mediated induction of TNFα and iNOS in the heart was not affected by aging, they may not be the primary factors contributing to the age-associated cardiovascular dysfunction and high mortality during systemic inflammation. IL-6 forms a complex with its specific receptor and a membrane glycoprotein (gp130) to exert its activity through two known signal pathways; one activates the transcription factor STAT3 via the Janus tyrosine kinases, and the other activates NF/IL6 (or CAAT/enhancer-binding protein) transcription factors via Ras and mitogen-activated protein kinase. Several stress response genes are induced by IL-6 via these gp130 pathways (41Kishimoto T. Taga T. Akira S. Cell. 1994; 76: 253-262Abstract Full Text PDF PubMed Scopus (1248) Google Scholar, 42Heinrich P.C. Behrmann I. Muller-Newen G. Schaper F. Graeve L. Biochem. J. 1998; 334: 297-314Crossref PubMed Scopus (1749) Google Scholar). Therefore, overexpression of IL-6 in aged cardiovascular tissues may result in overexpression of various stress response genes. Identification of such stress response genes should provide important information on altered biochemical mechanisms in aged animals in response to endotoxic stress. In conclusion, IL-6 is strongly induced in the heart, mostly in the microvascular walls, during endotoxic stress, and this induction is significantly augmented and prolonged with aging. The cardiac gene expression of IL-1β and ICAM-1 is also elevated or extended with aging during endotoxic stress. We propose such increased intensity and/or duration of the expression of inflammatory genes as important characteristics of aging that may be causally associated with the elevated susceptibility in aged subjects to inflammatory stress. We are grateful to Drs. M. S. Runge, C. Patterson, S. Waxman, Z. Hu, and S. Yamamoto for immunohistochemical studies. We also thank Drs. D. A. Konkel and S. Yamamoto for critically reading the manuscript." @default.
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