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Departments of
*
Medicine and
Surgery, University of Colorado Health Sciences Center, Denver, CO 80262; and Departments of
Medicine and
§
Rheumatology, University Hospital, Nijmegen, The Netherlands
In addition to stimulating IFN-
synthesis, IL-18 also possesses
inflammatory effects by inducing synthesis of the proinflammatory
cytokines TNF and IL-1ß and the chemokines IL-8 and macrophage
inflammatory protein-1
. We hypothesized that neutralization of IL-18
would have a beneficial effect in lethal endotoxemia in mice. IL-1ß
converting enzyme (ICE)-deficient mice, lacking the ability to process
mature IL-18 and IL-1ß, were completely resistant to lethal
endotoxemia induced by LPS derived from either Escherichia
coli or Salmonella typhimurium. In contrast,
both wild-type and IL-1ß-/- mice were equally
susceptible to the lethal effects of LPS, implicating that absence of
mature IL-18 or IFN- but not IL-1ß in ICE-/- mice is
responsible for this resistance. However, IFN--deficient mice were
not resistant to S. typhimurium LPS, suggesting an
IFN--independent role for IL-18. Anti-IL-18 Abs protected mice
against a lethal injection of either LPS. Anti-IL-18 treatment also
reduced neutrophil accumulation in liver and lungs. The increased
survival was accompanied by decreased levels of IFN- and macrophage
inflammatory protein-2 in anti-IL-18-treated animals challenged
with E. coli LPS, whereas IFN- and TNF concentrations
were decreased in treated mice challenged with S.
typhimurium. In conclusion, neutralization of IL-18 during
lethal endotoxemia protects mice against lethal effects of LPS. This
protection is partly mediated through inhibition of IFN- production,
but mechanisms involving decreased neutrophil-mediated tissue damage
due to the reduction of either chemokines (E. coli LPS)
or TNF (S. typhimurium LPS) synthesis by anti-IL-18
treatment may also be involved.
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J. Fierer, M. A. Swancutt, D. Heumann, and D. Golenbock The Role of Lipopolysaccharide Binding Protein in Resistance to Salmonella Infections in Mice J. Immunol., June 15, 2002; 168(12): 6396 - 6403. [Abstract] [Full Text] [PDF]
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R. J. L. Stuyt, M. G. Netea, I. Verschueren, G. Fantuzzi, C. A. Dinarello, J. W. M. Van der Meer, and B. J. Kullberg Role of Interleukin-18 in Host Defense against Disseminated Candida albicans Infection Infect. Immun., June 1, 2002; 70(6): 3284 - 3286. [Abstract] [Full Text] [PDF]
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X. Huang, S. A. McClellan, R. P. Barrett, and L. D. Hazlett IL-18 Contributes to Host Resistance Against Infection with Pseudomonas aeruginosa Through Induction of IFN-{gamma} Production J. Immunol., June 1, 2002; 168(11): 5756 - 5763. [Abstract] [Full Text] [PDF]
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 H. Tanaka, M. Narita, S. Teramoto, T. Saikai, K. Oashi, T. Igarashi, and S. Abe Role of Interleukin-18 and T-helper Type 1 Cytokines in the Development of Mycoplasma pneumoniae Pneumonia in Adults* Chest, May 1, 2002; 121(5): 1493 - 1497. [Abstract] [Full Text] [PDF]
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B. Wang, C. Feliciani, B. G. Howell, I. Freed, Q. Cai, H. Watanabe, and D. N. Sauder Contribution of Langerhans Cell-Derived IL-18 to Contact Hypersensitivity J. Immunol., April 1, 2002; 168(7): 3303 - 3308. [Abstract] [Full Text] [PDF]
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 R. L. Santos, S. Zhang, R. M. Tsolis, A. J. Baumler, and L. G. Adams Morphologic and Molecular Characterization of Salmonella typhimurium Infection in Neonatal Calves Vet. Pathol., March 1, 2002; 39(2): 200 - 215. [Abstract] [Full Text] [PDF]
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 M. Okamoto, S. Kato, K. Oizumi, M. Kinoshita, Y. Inoue, K. Hoshino, S. Akira, A. N. J. Mckenzie, H. A. Young, and T. Hoshino Interleukin 18 (IL-18) in synergy with IL-2 induces lethal lung injury in mice: a potential role for cytokines, chemokines, and natural killer cells in the pathogenesis of interstitial pneumonia Blood, February 15, 2002; 99(4): 1289 - 1298. [Abstract] [Full Text] [PDF]
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F. N. Lauw, J. Branger, S. Florquin, P. Speelman, S. J. H. van Deventer, S. Akira, and T. van der Poll IL-18 Improves the Early Antimicrobial Host Response to Pneumococcal Pneumonia J. Immunol., January 1, 2002; 168(1): 372 - 378. [Abstract] [Full Text] [PDF]
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R. Faggioni, R. C. Cattley, J. Guo, S. Flores, H. Brown, M. Qi, S. Yin, D. Hill, S. Scully, C. Chen, et al. IL-18-Binding Protein Protects Against Lipopolysaccharide- Induced Lethality and Prevents the Development of Fas/Fas Ligand-Mediated Models of Liver Disease in Mice J. Immunol., November 15, 2001; 167(10): 5913 - 5920. [Abstract] [Full Text] [PDF]
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 C A Dinarello Novel targets for interleukin 18 binding protein Ann Rheum Dis, November 1, 2001; 60(90003): iii18 - 24. [Abstract] [Full Text] [PDF]
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D. G. Mordue, F. Monroy, M. La Regina, C. A. Dinarello, and L. D. Sibley Acute Toxoplasmosis Leads to Lethal Overproduction of Th1 Cytokines J. Immunol., October 15, 2001; 167(8): 4574 - 4584. [Abstract] [Full Text] [PDF]
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F. N. Lauw, S. Florquin, P. Speelman, S. J. H. van Deventer, and T. van der Poll Role of Endogenous Interleukin-12 in Immune Response to Staphylococcal Enterotoxin B in Mice Infect. Immun., September 1, 2001; 69(9): 5949 - 5952. [Abstract] [Full Text] [PDF]
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B. P. Leung, S. Culshaw, J. A. Gracie, D. Hunter, C. A. Canetti, C. Campbell, F. Cunha, F. Y. Liew, and I. B. McInnes A Role for IL-18 in Neutrophil Activation J. Immunol., September 1, 2001; 167(5): 2879 - 2886. [Abstract] [Full Text] [PDF]
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L. A. B. Joosten, F. A. J. van de Loo, E. Lubberts, M. M. A. Helsen, M. G. Netea, J. W. M. van der Meer, C. A. Dinarello, and W. B. van den Berg An IFN-{gamma}-Independent Proinflammatory Role of IL-18 in Murine Streptococcal Cell Wall Arthritis J. Immunol., December 1, 2000; 165(11): 6553 - 6558. [Abstract] [Full Text] [PDF]
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 M. Narita, H. Tanaka, S. Abe, S. Yamada, M. Kubota, and T. Togashi Close Association between Pulmonary Disease Manifestation in Mycoplasma pneumoniae Infection and Enhanced Local Production of Interleukin-18 in the Lung, Independent of Gamma Interferon Clin. Vaccine Immunol., November 1, 2000; 7(6): 909 - 914. [Abstract] [Full Text] [PDF]
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C. A Dinarello Targeting interleukin 18 with interleukin 18 binding protein Ann Rheum Dis, November 1, 2000; 59(90001): i17 - 20. [Abstract] [Full Text] [PDF]
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