Endogenous Interleukin-6 Plays a Crucial Protective Role in Streptococcal Toxic Shock Syndrome via Suppression of Tumor Necrosis Factor Alph
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感染与免疫杂志 2005年第6期
Division of Molecular Immunology, Institute for Genetic Medicine
Department of Microbiology, School of Medicine, Hokkaido University, Sapporo, Japan
ABSTRACT
During a Streptococcus pyogenes infection in interleukin-6 (IL-6)-deficient mice, there is elevation of serum tumor necrosis factor alpha (TNF-) levels, muscular necrosis, and death compared with infection of C57BL/6 mice. Anti-TNF- monoclonal antibody treatment decreased mortality and muscular necrosis in the infected IL-6-deficient mice. These results suggest that IL-6 plays a crucial protective role via suppression of TNF- production in S. pyogenes infection.
TEXT
A streptococcal toxic shock syndrome (STSS) due to group A streptococcus (GAS) (Streptococcus pyogenes) was reported in the late 1980s (4). Since then the number of patients with this serious infectious disease has been increasing in North America, Europe, and other parts of the world (5, 11). STSS caused by GAS was characterized as a severe infectious disease which progresses to septic shock and multiple organ failure, with a frequent occurrence of necrotizing fasciitis. STSS is associated with a very high mortality rate and remains a serious concern in the clinical setting (7). It is thought that cytokine production is important in inducing STSS (10). It is recognized that interleukin-6 (IL-6) is detected in the sera of STSS patients (10). Therefore, it is possible that IL-6 plays a crucial role in STSS. IL-6 is known as an proinflammatory cytokine and induces many immunobiological reactions (2). However, it is reported that IL-6 plays a role in both the promotion (3) and the suppression (16) of immunological reactions. On the other hand, IL-6 induces production of acute-phase reactants, which are serum proteins synthesized by hepatocytes (17), and suppresses immune reactions (13). Therefore, the role of IL-6 in infectious diseases is not clear. To clarify the role of IL-6 in S. pyogenes infection, we observed the mortality rates and bacterial growth in the infected sites of IL-6–/– and IL-6+/+mice. Muscular necrosis is one of the peculiar symptoms of invasive streptococcal infection and STSS (7), so we inoculated S. pyogenes into the muscles of mice to induce muscular necrosis.
Female C57BL/6 (IL-6+/+) and IL-6-deficient (IL-6–/–) mice, aged 8 weeks, were used. IL-6+/+ mice were purchased from SLC (Hamamatsu, Shizuoka, Japan), and IL-6–/– mice on the C57BL/6 background were purchased from The Jackson Laboratory (Bar Harbor, Maine). Mice were infected in the right thigh muscle with 0.1 ml of a solution containing 5 x 108 CFU of viable S. pyogenes cells in phosphate-buffered saline. The S. pyogenes strain used was a clinical isolate from a patient with pharyngitis in Hokkaido University Hospital, Sapporo, Japan. The bacteria were type M12/T12. M and T typing was kindly performed by A. Tamaru at the Osaka Prefectural Institution of Public Health, Osaka, Japan. The strain was stored as stock cultures at –80°C in Todd-Hewitt broth (Difco Laboratories, Detroit, Mich.); when needed, cultures from frozen stocks were grown in 200 ml of Todd-Hewitt broth and incubated for 10 h at 37°C, and the bacteria were harvested at the start of the stationary phase. The right thigh muscles of infected animals were excised at 24 h postinfection (p.i.), cut up with scissors, and homogenized in a tissue homogenizer (type NS-310E, PHYSOOTRON) (6). Serial 10-fold dilutions of the organ suspensions were placed on blood agar plates and incubated at 37°C for 24 h; then the number of colonies was counted.
Levels of tumor necrosis factor- (TNF-) and IL-6 were determined by use of sandwich enzyme-linked immunosorbent assays (ELISA) as described previously (9). For investigation of the role of endogenous TNF- in S. pyogenes infection, we performed an experiment in which an anti-TNF- monoclonal antibody (MAb) was administered. A hybridoma cell line secreting a MAb against mouse TNF- (MP6-XT22.11; rat immunoglobulin G1) (9) was used. Mice were given a single intravenous injection of the MAb 2 h before infection. Normal rat globulin (NRG) was injected as a control for the MAb. NRG was prepared as described previously (6). IL-6–/– mice were given a single intravenous injection of 1 μg of recombinant mouse IL-6 (rmIL-6) (Genzyme) simultaneously with infection. Phosphate-buffered saline was injected as a control for rmIL-6.
First, we observed the kinetics of endogenous IL-6 when mice were inoculated intramuscularly with S. pyogenes. IL-6 could be detected in serum from 2 h until 48 h after infection in IL-6+/+ mice infected with S. pyogenes. Peak serum IL-6 titers were observed at 8 h p.i. (Fig. 1a). IL-6 was not detected in the sera of IL-6–/– mice infected with S. pyogenes (data not shown). Because IL-6 was produced in infected IL-6+/+ mice, IL-6 might be involved in S. pyogenes infection. To clarify the role of IL-6, we compared IL-6–/– and IL-6+/+ mice in this study. All of the IL-6+/+ mice infected with 5 x 108 CFU of viable S. pyogenes survived until day 10 p.i. (Fig. 1b). On the other hand, the mortality rate of infected IL-6–/– mice was 70% on day 10 p.i. (Fig. 1b). Muscular necrosis was observed in 20% of infected IL-6–/– mice but not in infected IL-6+/+ mice (data not shown). Our previous study showed that the numbers of S. pyogenes bacteria in the thigh muscle peaked at 24 h after infection (6). Therefore, the bacterial numbers in the muscle tissues of infected IL-6–/– and IL-6+/+ mice were determined at 24 h after infection in this study (Fig. 1c). The numbers of bacteria in infected muscles of IL-6–/– mice were significantly larger than those in IL-6+/+ mice at 24 h p.i (Fig. 1c). To investigate pathological changes in the muscles of the infected mice, we performed a histological study. Infected IL-6–/– mice showed necrosis of muscles and less infiltration of leukocytes; infected IL-6+/+ mice showed only infiltration of leukocytes into the muscles (Fig. 1d). These data indicate that IL-6 deficiency rendered mice susceptible to intramuscular infection of S. pyogenes and to muscular necrosis and death. These appearances of infected IL-6–/– mice are similar to symptoms of human STSS. To further investigate the role of IL-6 produced in muscular infection with S. pyogenes, we investigated whether administration of rmIL-6 to the IL-6–/– mice infected with S. pyogenes improved the outcome of streptococcal diseases or not. Administration of 1 μg of rmIL-6 completely inhibited death and muscular necrosis (data not shown).
We previously reported that TNF- caused deterioration in cases of streptococcal infection (6). Therefore, we investigated serum TNF- levels in infected mice. Serum TNF- titers in infected IL-6–/– mice were significantly higher than those in infected IL-6+/+ mice (Fig. 2a). Administration of 1 μg of rmIL-6 to IL-6–/– mice inhibited elevation of serum TNF- (Fig. 2b). For investigation of the role of endogenous TNF- in IL-6–/– mice, we performed an anti-TNF- MAb administration experiment. The mortality rate and muscular necrosis decreased with anti-TNF- MAb treatment (Table 1). NRG, which was injected as a control for the MAb, had no effect on the mortality rate or muscular necrosis.
IL-6 is known as a proinflammatory cytokine in immune reactions. However, until now, it has remained unclear how endogenous IL-6 inhibits endogenous TNF- production in streptococcal infection. We investigated whether endogenous IL-6 in streptococcal infection acts directly on immunocompetent cells or not. Titers of TNF- produced by IL-6–/– mouse splenocytes stimulated with heat-killed S. pyogenes were significantly higher than those from IL-6+/+ mouse splenocytes (Fig. 3a). Splenocytes from IL-6–/– mice were incubated with varying doses of rmIL-6 (0.1 ng, 1 ng, 10 ng, 100 ng, and 1,000 ng). The low-dose rmIL-6 (0.1 ng) treatment significantly reduced TNF- levels in IL-6–/– mouse splenocytes stimulated with heat-killed S. pyogenes (Fig. 3b). In addition, TNF- levels tended to be lower with increasing doses of rmIL-6 in splenocytes from IL-6–/– mice (Fig. 3b). Moreover, rmIL-6 also inhibited TNF- production in IL-6+/+ mouse splenocytes (data not shown). This indicates that IL-6 suppresses TNF- production by immunocompetent cells.
It is recognized that IL-6 is a proinflammatory cytokine and augments inflammatory reactions (2). On the other hand, it has been reported that IL-6 inhibits inflammatory reactions in vivo (8, 12) and in vitro (18). Recently, it was also reported that IL-6 acts as an anti-inflammatory cytokine and suppresses TNF- production in SOCS3 gene knockout mice (18). Our present study shows that TNF- production by splenocytes stimulated with heat-killed S. pyogenes was inhibited by IL-6. This indicates that IL-6 regulates TNF- production in immunocompetent cells.
Streptococcal infection is sometimes curable by antibiotic therapy. However, S. pyogenes also causes severe streptococcal disease which cannot be controlled by antibiotics. It has been reported that a superantigen is important in inducing STSS (15). In STSS, bacterial cells proliferate dramatically in the host. This indicates that cytokines, which are produced by the stimulation of the superantigen, induce bacterial growth in the host. Therefore, we speculated that an inhibitory mechanism of cytokine production exists in nonsevere streptococcal infection. It is possible that STSS is triggered by a decrease in IL-6 production and that administration of recombinant IL-6 would be effective in the treatment of severe streptococcal infection.
Our present study shows that IL-6 plays an important role in the negative feedback of the immune reaction in the early phase of infectious disease. It has been reported that IL-6 is necessary to regulate excessive cytokine production in some infectious diseases (1, 8, 14). We expect that administration of IL-6 will be effective in treatment against the cytokine storm, which occurs in severe infection and trauma.
REFERENCES
1. Abe, J., J. Forrester, T. Nakahara, J. A. Lafferty, B. L. Kotzin, and D. Y. Leung. 1991. Selective stimulation of human T cells with streptococcal erythrogenic toxins A and B. J. Immunol. 146:3747-3750.
2. Alonzi, T., E. Fattori, D. Lazzaro, P. Costa, L. Probert, G. Kollias, F. De Benedetti, V. Poli, and G. Ciliberto. 1998. Interleukin 6 is required for the development of collagen-induced arthritis. J. Exp. Med. 187:461-468.
3. Cheung, W. C., and B. Van Ness. 2002. Distinct IL-6 signal transduction leads to growth arrest and death in B cells or growth promotion and cell survival in myeloma cells. Leukemia 16:1182-1188.
4. Cone, L. A., D. R. Woodard, P. M. Schlievert, and G. S. Tomory. 1987. Clinical and bacteriologic observations of a toxic shock-like syndrome due to Streptococcus pyogenes. N. Engl. J. Med. 317:146-149.
5. Davies, H. D., A. McGeer, B. Schwartz, K. Green, D. Cann, A. E. Simor, D. E. Low, et al. 1996. Invasive group A streptococcal infections in Ontario, Canada. N. Engl. J. Med. 335:547-554.
6. Diao, H., M. Kohanawa, Yimin, H. Nakajima, Y. Sato, T. Minagawa, and A. Nakane. 2002. Lipopolysaccharide triggers invasive streptococcal disease in mice through a tumour necrosis factor-alpha-dependent mechanism. Immunology 105:344-349.
7. Eriksson, B. K., J. Andersson, S. E. Holm, and M. Norgren. 1998. Epidemiological and clinical aspects of invasive group A streptococcal infections and the streptococcal toxic shock syndrome. Clin. Infect. Dis. 27:1428-1436.
8. Mancuso, G., F. Tomasello, M. Migliardo, D. Delfino, J. Cochran, J. A. Cook, and G. Teti. 1994. Beneficial effects of interleukin-6 in neonatal mouse models of group B streptococcal disease. Infect. Immun. 62:4997-5002.
9. Nakane, A., T. Minagawa, and K. Kato. 1988. Endogenous tumor necrosis factor (cachectin) is essential to host resistance against Listeria monocytogenes infection. Infect. Immun. 56:2563-2569.
10. Norrby-Teglund, A., K. Pauksens, M. Norgren, and S. E. Holm. 1995. Correlation between serum TNF and IL6 levels and severity of group A streptococcal infections. Scand. J. Infect. Dis. 27:125-130.
11. O'Brien, K. L., B. Beall, N. L. Barrett, P. R. Cieslak, A. Reingold, M. M. Farley, R. Danila, E. R. Zell, R. Facklam, B. Schwartz, and A. Schuchat. 2002. Epidemiology of invasive group A streptococcus disease in the United States, 1995-1999. Clin. Infect. Dis. 35:268-276.
12. Pallua, N., J. F. Low, and D. von Heimburg. 2003. Pathogenic role of interleukin-6 in the development of sepsis. Part II. Significance of anti-interleukin-6 and anti-soluble interleukin-6 receptor-alpha antibodies in a standardized murine contact burn model. Crit. Care Med. 31:1495-1501.
13. Paul, R., U. Koedel, F. Winkler, B. C. Kieseier, A. Fontana, M. Kopf, H. P. Hartung, and H. W. Pfister. 2003. Lack of IL-6 augments inflammatory response but decreases vascular permeability in bacterial meningitis. Brain 126:1873-1882.
14. Schindler, R., J. Mancilla, S. Endres, R. Ghorbani, S. C. Clark, and C. A. Dinarello. 1990. Correlations and interactions in the production of interleukin-6 (IL-6), IL-1, and tumor necrosis factor (TNF) in human blood mononuclear cells: IL-6 suppresses IL-1 and TNF. Blood 75:40-47.
15. Talkington, D. F., B. Schwartz, C. M. Black, J. K. Todd, J. Elliott, R. F. Breiman, and R. R. Facklam. 1993. Association of phenotypic and genotypic characteristics of invasive Streptococcus pyogenes isolates with clinical components of streptococcal toxic shock syndrome. Infect. Immun. 61:3369-3374.
16. Taylor, S., S. Shacks, and Z. Qu. 2001. Effect of anti-IL-6 and anti-10 monoclonal antibodies on the suppression of the normal T lymphocyte mitogenic response by steady state sickle cell disease sera. Immunol. Investig. 30:209-219.
17. Wu, X., D. N. Herndon, and S. E. Wolf. 2003. Growth hormone down-regulation of interleukin-1 and interleukin-6 induced acute phase protein gene expression is associated with increased gene expression of suppressor of cytokine signal-3. Shock 19:314-320.
18. Yasukawa, H., M. Ohishi, H. Mori, M. Murakami, T. Chinen, D. Aki, T. Hanada, K. Takeda, S. Akira, M. Hoshijima, T. Hirano, K. R. Chien, and A. Yoshimura. 2003. IL-6 induces an anti-inflammatory response in the absence of SOCS3 in macrophages. Nat. Immunol. 4:551-556.(Hongyan Diao and Masashi )
Department of Microbiology, School of Medicine, Hokkaido University, Sapporo, Japan
ABSTRACT
During a Streptococcus pyogenes infection in interleukin-6 (IL-6)-deficient mice, there is elevation of serum tumor necrosis factor alpha (TNF-) levels, muscular necrosis, and death compared with infection of C57BL/6 mice. Anti-TNF- monoclonal antibody treatment decreased mortality and muscular necrosis in the infected IL-6-deficient mice. These results suggest that IL-6 plays a crucial protective role via suppression of TNF- production in S. pyogenes infection.
TEXT
A streptococcal toxic shock syndrome (STSS) due to group A streptococcus (GAS) (Streptococcus pyogenes) was reported in the late 1980s (4). Since then the number of patients with this serious infectious disease has been increasing in North America, Europe, and other parts of the world (5, 11). STSS caused by GAS was characterized as a severe infectious disease which progresses to septic shock and multiple organ failure, with a frequent occurrence of necrotizing fasciitis. STSS is associated with a very high mortality rate and remains a serious concern in the clinical setting (7). It is thought that cytokine production is important in inducing STSS (10). It is recognized that interleukin-6 (IL-6) is detected in the sera of STSS patients (10). Therefore, it is possible that IL-6 plays a crucial role in STSS. IL-6 is known as an proinflammatory cytokine and induces many immunobiological reactions (2). However, it is reported that IL-6 plays a role in both the promotion (3) and the suppression (16) of immunological reactions. On the other hand, IL-6 induces production of acute-phase reactants, which are serum proteins synthesized by hepatocytes (17), and suppresses immune reactions (13). Therefore, the role of IL-6 in infectious diseases is not clear. To clarify the role of IL-6 in S. pyogenes infection, we observed the mortality rates and bacterial growth in the infected sites of IL-6–/– and IL-6+/+mice. Muscular necrosis is one of the peculiar symptoms of invasive streptococcal infection and STSS (7), so we inoculated S. pyogenes into the muscles of mice to induce muscular necrosis.
Female C57BL/6 (IL-6+/+) and IL-6-deficient (IL-6–/–) mice, aged 8 weeks, were used. IL-6+/+ mice were purchased from SLC (Hamamatsu, Shizuoka, Japan), and IL-6–/– mice on the C57BL/6 background were purchased from The Jackson Laboratory (Bar Harbor, Maine). Mice were infected in the right thigh muscle with 0.1 ml of a solution containing 5 x 108 CFU of viable S. pyogenes cells in phosphate-buffered saline. The S. pyogenes strain used was a clinical isolate from a patient with pharyngitis in Hokkaido University Hospital, Sapporo, Japan. The bacteria were type M12/T12. M and T typing was kindly performed by A. Tamaru at the Osaka Prefectural Institution of Public Health, Osaka, Japan. The strain was stored as stock cultures at –80°C in Todd-Hewitt broth (Difco Laboratories, Detroit, Mich.); when needed, cultures from frozen stocks were grown in 200 ml of Todd-Hewitt broth and incubated for 10 h at 37°C, and the bacteria were harvested at the start of the stationary phase. The right thigh muscles of infected animals were excised at 24 h postinfection (p.i.), cut up with scissors, and homogenized in a tissue homogenizer (type NS-310E, PHYSOOTRON) (6). Serial 10-fold dilutions of the organ suspensions were placed on blood agar plates and incubated at 37°C for 24 h; then the number of colonies was counted.
Levels of tumor necrosis factor- (TNF-) and IL-6 were determined by use of sandwich enzyme-linked immunosorbent assays (ELISA) as described previously (9). For investigation of the role of endogenous TNF- in S. pyogenes infection, we performed an experiment in which an anti-TNF- monoclonal antibody (MAb) was administered. A hybridoma cell line secreting a MAb against mouse TNF- (MP6-XT22.11; rat immunoglobulin G1) (9) was used. Mice were given a single intravenous injection of the MAb 2 h before infection. Normal rat globulin (NRG) was injected as a control for the MAb. NRG was prepared as described previously (6). IL-6–/– mice were given a single intravenous injection of 1 μg of recombinant mouse IL-6 (rmIL-6) (Genzyme) simultaneously with infection. Phosphate-buffered saline was injected as a control for rmIL-6.
First, we observed the kinetics of endogenous IL-6 when mice were inoculated intramuscularly with S. pyogenes. IL-6 could be detected in serum from 2 h until 48 h after infection in IL-6+/+ mice infected with S. pyogenes. Peak serum IL-6 titers were observed at 8 h p.i. (Fig. 1a). IL-6 was not detected in the sera of IL-6–/– mice infected with S. pyogenes (data not shown). Because IL-6 was produced in infected IL-6+/+ mice, IL-6 might be involved in S. pyogenes infection. To clarify the role of IL-6, we compared IL-6–/– and IL-6+/+ mice in this study. All of the IL-6+/+ mice infected with 5 x 108 CFU of viable S. pyogenes survived until day 10 p.i. (Fig. 1b). On the other hand, the mortality rate of infected IL-6–/– mice was 70% on day 10 p.i. (Fig. 1b). Muscular necrosis was observed in 20% of infected IL-6–/– mice but not in infected IL-6+/+ mice (data not shown). Our previous study showed that the numbers of S. pyogenes bacteria in the thigh muscle peaked at 24 h after infection (6). Therefore, the bacterial numbers in the muscle tissues of infected IL-6–/– and IL-6+/+ mice were determined at 24 h after infection in this study (Fig. 1c). The numbers of bacteria in infected muscles of IL-6–/– mice were significantly larger than those in IL-6+/+ mice at 24 h p.i (Fig. 1c). To investigate pathological changes in the muscles of the infected mice, we performed a histological study. Infected IL-6–/– mice showed necrosis of muscles and less infiltration of leukocytes; infected IL-6+/+ mice showed only infiltration of leukocytes into the muscles (Fig. 1d). These data indicate that IL-6 deficiency rendered mice susceptible to intramuscular infection of S. pyogenes and to muscular necrosis and death. These appearances of infected IL-6–/– mice are similar to symptoms of human STSS. To further investigate the role of IL-6 produced in muscular infection with S. pyogenes, we investigated whether administration of rmIL-6 to the IL-6–/– mice infected with S. pyogenes improved the outcome of streptococcal diseases or not. Administration of 1 μg of rmIL-6 completely inhibited death and muscular necrosis (data not shown).
We previously reported that TNF- caused deterioration in cases of streptococcal infection (6). Therefore, we investigated serum TNF- levels in infected mice. Serum TNF- titers in infected IL-6–/– mice were significantly higher than those in infected IL-6+/+ mice (Fig. 2a). Administration of 1 μg of rmIL-6 to IL-6–/– mice inhibited elevation of serum TNF- (Fig. 2b). For investigation of the role of endogenous TNF- in IL-6–/– mice, we performed an anti-TNF- MAb administration experiment. The mortality rate and muscular necrosis decreased with anti-TNF- MAb treatment (Table 1). NRG, which was injected as a control for the MAb, had no effect on the mortality rate or muscular necrosis.
IL-6 is known as a proinflammatory cytokine in immune reactions. However, until now, it has remained unclear how endogenous IL-6 inhibits endogenous TNF- production in streptococcal infection. We investigated whether endogenous IL-6 in streptococcal infection acts directly on immunocompetent cells or not. Titers of TNF- produced by IL-6–/– mouse splenocytes stimulated with heat-killed S. pyogenes were significantly higher than those from IL-6+/+ mouse splenocytes (Fig. 3a). Splenocytes from IL-6–/– mice were incubated with varying doses of rmIL-6 (0.1 ng, 1 ng, 10 ng, 100 ng, and 1,000 ng). The low-dose rmIL-6 (0.1 ng) treatment significantly reduced TNF- levels in IL-6–/– mouse splenocytes stimulated with heat-killed S. pyogenes (Fig. 3b). In addition, TNF- levels tended to be lower with increasing doses of rmIL-6 in splenocytes from IL-6–/– mice (Fig. 3b). Moreover, rmIL-6 also inhibited TNF- production in IL-6+/+ mouse splenocytes (data not shown). This indicates that IL-6 suppresses TNF- production by immunocompetent cells.
It is recognized that IL-6 is a proinflammatory cytokine and augments inflammatory reactions (2). On the other hand, it has been reported that IL-6 inhibits inflammatory reactions in vivo (8, 12) and in vitro (18). Recently, it was also reported that IL-6 acts as an anti-inflammatory cytokine and suppresses TNF- production in SOCS3 gene knockout mice (18). Our present study shows that TNF- production by splenocytes stimulated with heat-killed S. pyogenes was inhibited by IL-6. This indicates that IL-6 regulates TNF- production in immunocompetent cells.
Streptococcal infection is sometimes curable by antibiotic therapy. However, S. pyogenes also causes severe streptococcal disease which cannot be controlled by antibiotics. It has been reported that a superantigen is important in inducing STSS (15). In STSS, bacterial cells proliferate dramatically in the host. This indicates that cytokines, which are produced by the stimulation of the superantigen, induce bacterial growth in the host. Therefore, we speculated that an inhibitory mechanism of cytokine production exists in nonsevere streptococcal infection. It is possible that STSS is triggered by a decrease in IL-6 production and that administration of recombinant IL-6 would be effective in the treatment of severe streptococcal infection.
Our present study shows that IL-6 plays an important role in the negative feedback of the immune reaction in the early phase of infectious disease. It has been reported that IL-6 is necessary to regulate excessive cytokine production in some infectious diseases (1, 8, 14). We expect that administration of IL-6 will be effective in treatment against the cytokine storm, which occurs in severe infection and trauma.
REFERENCES
1. Abe, J., J. Forrester, T. Nakahara, J. A. Lafferty, B. L. Kotzin, and D. Y. Leung. 1991. Selective stimulation of human T cells with streptococcal erythrogenic toxins A and B. J. Immunol. 146:3747-3750.
2. Alonzi, T., E. Fattori, D. Lazzaro, P. Costa, L. Probert, G. Kollias, F. De Benedetti, V. Poli, and G. Ciliberto. 1998. Interleukin 6 is required for the development of collagen-induced arthritis. J. Exp. Med. 187:461-468.
3. Cheung, W. C., and B. Van Ness. 2002. Distinct IL-6 signal transduction leads to growth arrest and death in B cells or growth promotion and cell survival in myeloma cells. Leukemia 16:1182-1188.
4. Cone, L. A., D. R. Woodard, P. M. Schlievert, and G. S. Tomory. 1987. Clinical and bacteriologic observations of a toxic shock-like syndrome due to Streptococcus pyogenes. N. Engl. J. Med. 317:146-149.
5. Davies, H. D., A. McGeer, B. Schwartz, K. Green, D. Cann, A. E. Simor, D. E. Low, et al. 1996. Invasive group A streptococcal infections in Ontario, Canada. N. Engl. J. Med. 335:547-554.
6. Diao, H., M. Kohanawa, Yimin, H. Nakajima, Y. Sato, T. Minagawa, and A. Nakane. 2002. Lipopolysaccharide triggers invasive streptococcal disease in mice through a tumour necrosis factor-alpha-dependent mechanism. Immunology 105:344-349.
7. Eriksson, B. K., J. Andersson, S. E. Holm, and M. Norgren. 1998. Epidemiological and clinical aspects of invasive group A streptococcal infections and the streptococcal toxic shock syndrome. Clin. Infect. Dis. 27:1428-1436.
8. Mancuso, G., F. Tomasello, M. Migliardo, D. Delfino, J. Cochran, J. A. Cook, and G. Teti. 1994. Beneficial effects of interleukin-6 in neonatal mouse models of group B streptococcal disease. Infect. Immun. 62:4997-5002.
9. Nakane, A., T. Minagawa, and K. Kato. 1988. Endogenous tumor necrosis factor (cachectin) is essential to host resistance against Listeria monocytogenes infection. Infect. Immun. 56:2563-2569.
10. Norrby-Teglund, A., K. Pauksens, M. Norgren, and S. E. Holm. 1995. Correlation between serum TNF and IL6 levels and severity of group A streptococcal infections. Scand. J. Infect. Dis. 27:125-130.
11. O'Brien, K. L., B. Beall, N. L. Barrett, P. R. Cieslak, A. Reingold, M. M. Farley, R. Danila, E. R. Zell, R. Facklam, B. Schwartz, and A. Schuchat. 2002. Epidemiology of invasive group A streptococcus disease in the United States, 1995-1999. Clin. Infect. Dis. 35:268-276.
12. Pallua, N., J. F. Low, and D. von Heimburg. 2003. Pathogenic role of interleukin-6 in the development of sepsis. Part II. Significance of anti-interleukin-6 and anti-soluble interleukin-6 receptor-alpha antibodies in a standardized murine contact burn model. Crit. Care Med. 31:1495-1501.
13. Paul, R., U. Koedel, F. Winkler, B. C. Kieseier, A. Fontana, M. Kopf, H. P. Hartung, and H. W. Pfister. 2003. Lack of IL-6 augments inflammatory response but decreases vascular permeability in bacterial meningitis. Brain 126:1873-1882.
14. Schindler, R., J. Mancilla, S. Endres, R. Ghorbani, S. C. Clark, and C. A. Dinarello. 1990. Correlations and interactions in the production of interleukin-6 (IL-6), IL-1, and tumor necrosis factor (TNF) in human blood mononuclear cells: IL-6 suppresses IL-1 and TNF. Blood 75:40-47.
15. Talkington, D. F., B. Schwartz, C. M. Black, J. K. Todd, J. Elliott, R. F. Breiman, and R. R. Facklam. 1993. Association of phenotypic and genotypic characteristics of invasive Streptococcus pyogenes isolates with clinical components of streptococcal toxic shock syndrome. Infect. Immun. 61:3369-3374.
16. Taylor, S., S. Shacks, and Z. Qu. 2001. Effect of anti-IL-6 and anti-10 monoclonal antibodies on the suppression of the normal T lymphocyte mitogenic response by steady state sickle cell disease sera. Immunol. Investig. 30:209-219.
17. Wu, X., D. N. Herndon, and S. E. Wolf. 2003. Growth hormone down-regulation of interleukin-1 and interleukin-6 induced acute phase protein gene expression is associated with increased gene expression of suppressor of cytokine signal-3. Shock 19:314-320.
18. Yasukawa, H., M. Ohishi, H. Mori, M. Murakami, T. Chinen, D. Aki, T. Hanada, K. Takeda, S. Akira, M. Hoshijima, T. Hirano, K. R. Chien, and A. Yoshimura. 2003. IL-6 induces an anti-inflammatory response in the absence of SOCS3 in macrophages. Nat. Immunol. 4:551-556.(Hongyan Diao and Masashi )