The Impact of Prolonged Strenuous Endurance Exercise on Interleukin 18 and Interleukin 18 Binding Protein in Recreational Cyclists

Abstract

Interleukin 18 (IL-18) is an important pro-inflammatory cytokine in the early phase of human immune response to microbial infections. The influence of strenuous exercise on the intrinsic balance of IL-18 and its endogenous antagonist IL-18 binding protein (IL-18 BP) is unknown, but could be of major relevance for the athlete's immune function empirically and epidemiologically proven to be altered after exhaustive exertion. To study the effect of strenuous marathon cycling on the interaction of IL-18 and IL-18 BP we investigated 37 male, healthy, and well-trained amateur cyclists participating in the Ötztaler Radmarathon in Tyrol (distance: 230 km; cumulative altitude difference: 5500 m). IL-18 was measured by a commercially available ELISA-Kit and IL-18 BP by a novel IL-18 BP ELISA method. Free, unbound IL-18 was calculated according to a standard equation. The mean plasma level of IL-18 was 142.27 ± 21.85 pg/ml pre-race, remained nearly unchanged (124.35 ± 13.16 pg/ml; p = 1.0) immediately after competition (mean race time 9 h 38 min), but declined significantly 24 h afterward (62.92 ± 6.80 pg/ml; p = 0.002). The plasma levels of IL-18 BP increased considerably immediately after and kept on rising for the following 24 h (pre-race: 1.51 ± 0.20 ng/ml; immediately post-race: 3.84 ± 0.26 ng/ml, p < 0.001; 24 h post-race: 4.33 ± 0.42 ng/ml, p < 0.001). Therefore, the calculated free IL-18 was 122.06 ± 16.79 pg/ml pre-race, declined to 82.86 ± 8.59 (p = 0.05) immediately post-race and to 39.17 ± 3.76 pg/ml 24 h post-race (p < 0.001). The respective percentages of this post-exercise reduction in free IL-18 plasma levels were 32 % and 68 %. The present study reveals an exercise-induced significant decline in free IL-18 accompanied by an immediate up-regulation of IL-18 BP and decreased IL-18 in marathon cyclists. This down-regulation of free IL-18 may (i) limit the magnitude and duration of a too excessive inflammatory response to the exercise-induced tissue damage and (ii) on the other hand contribute to the elevated susceptibility to infection in athletes undergoing exhaustive exercise.

Key words

IL-18 - IL-18 BP - cytokine - endurance exercise - marathon cycling

References

• 1 Cho D, Song H, Kim Y M, Houh D, Hur D Y, Park H, Yoon D, Pyun K H, Lee W J, Kurimoto M, Kim Y B, Kim Y S, Choi I. Endogenous interleukin-18 modulates immune escape of murine melanoma cells by regulating the expression of Fas ligand and reactive oxygen intermediates.  Cancer Res. 2000;  60 2703-2709
• 2 Dao T, Mehal W Z, Crispe I N. IL-18 augments perforin-dependent cytotoxicity of liver NK-T cells.  J Immunol. 1998;  161 2217-2222
• 3 Dao T, Ohashi K, Kayano T, Kurimoto M, Okamura H. Interferon-gamma-inducing factor, a novel cytokine, enhances Fas ligand-mediated cytotoxicity of murine T helper 1 cells.  Cell Immunol. 1996;  173 230-235
• 4 Dinarello C A, Novick D, Puren A J, Fantuzzi G, Shapiro L, Muhl H, Yoon D Y, Reznikov L L, Kim S H, Rubinstein M. Overview of interleukin-18: more than an interferon-gamma inducing factor.  J Leukoc Biol. 1998;  63 658-664
• 5 Hashimoto W, Osaki T, Okamura H, Robbins P D, Kurimoto M, Nagata S, Lotze M T, Tahara H. Differential antitumor effects of administration of recombinant IL-18 or recombinant IL-12 are mediated primarily by Fas-Fas ligand- and perforin-induced tumor apoptosis, respectively.  J Immunol. 1999;  163 583-589
• 6 Hoshino K, Tsutsui H, Kawai T, Takeda K, Nakanishi K, Takeda Y, Akira S. Cutting edge: generation of IL-18 receptor-deficient mice: evidence for IL-1 receptor-related protein as an essential IL-18 binding receptor.  J Immunol. 1999;  162 5041-5044
• 7 Hyodo Y, Matsui K, Hayashi N, Tsutsui H, Kashiwamura S, Yamauchi H, Hiroishi K, Takeda K, Tagawa Y, Iwakura Y, Kayagaki N, Kurimoto M, Okamura H, Hada T, Yagita H, Akira S, Nakanishi K, Higashino K. IL-18 up-regulates perforin-mediated NK activity without increasing perforin messenger RNA expression by binding to constitutively expressed IL-18 receptor.  J Immunol. 1999;  162 1662-1668
• 8 Kinjo Y, Kawakami K, Uezu K, Yara S, Miyagi K, Koguchi Y, Hoshino T, Okamoto M, Kawase Y, Yokota K, Yoshino K, Takeda K, Akira S, Saito A. Contribution of IL-18 to Th1 response and host defense against infection by Mycobacterium tuberculosis: a comparative study with IL-12 p40.  J Immunol. 2002;  169 323-329
• 9 Kohno K, Kataoka J, Ohtsuki T, Suemoto Y, Okamoto I, Usui M, Ikeda M, Kurimoto M. IFN-gamma-inducing factor (IGIF) is a costimulatory factor on the activation of Th1 but not Th2 cells and exerts its effect independently of IL-12.  J Immunol. 1997;  158 1541-1550
• 10 Lauw F N, Branger J, Florquin S, Speelman P, van Deventer S J, Akira S, van der Poll T. IL-18 improves the early antimicrobial host response to pneumococcal pneumonia.  J Immunol. 2002;  168 372-378
• 11 Liu B, Mori I, Hossain M J, Dong L, Takeda K, Kimura Y. Interleukin-18 improves the early defence system against influenza virus infection by augmenting natural killer cell-mediated cytotoxicity.  J Gen Virol. 2004;  85 423-428
• 12 Micallef M J, Ohtsuki T, Kohno K, Tanabe F, Ushio S, Namba M, Tanimoto T, Torigoe K, Fujii M, Ikeda M, Fukuda S, Kurimoto M. Interferon-gamma-inducing factor enhances T helper 1 cytokine production by stimulated human T cells: synergism with interleukin-12 for interferon-gamma production.  Eur J Immunol. 1996;  26 1647-1651
• 13 Moldoveanu A I, Shephard R J, Shek P N. The cytokine response to physical activity and training.  Sports Med. 2001;  31 115-144
• 14 Neumayr G, Pfister R, Mitterbauer G, Gaenzer H, Sturm W, Eibl G, Hoertnagl H. Exercise intensity of cycle-touring events.  Int J Sports Med. 2002;  23 505-509
• 15 Nieman D C. Immune response to heavy exertion.  J Appl Physiol. 1997;  82 1385-1394
• 16 Nieman D C. Is infection risk linked to exercise workload?.  Med Sci Sports Exerc. 2000;  32 406-411
• 17 Novick D, Kim S H, Fantuzzi G, Reznikov L L, Dinarello C A, Rubinstein M. Interleukin-18 binding protein: a novel modulator of the Th1 cytokine response.  Immunity. 1999;  10 127-136
• 18 Novick D, Schwartsburd B, Pinkus R, Suissa D, Belzer I, Sthoeger Z, Keane W F, Chvatchko Y, Kim S H, Fantuzzi G, Dinarello C A, Rubinstein M. A novel il-18 bp elisa shows elevated serum il-18 bp in sepsis and extensive decrease of free il-18.  Cytokine. 2001;  14 334-342
• 19 Okamura H, Tsutsui H, Kashiwamura S, Yoshimoto T, Nakanishi K. Interleukin-18: a novel cytokine that augments both innate and acquired immunity.  Adv Immunol. 1998;  70 281-312
• 20 Okamura H, Nagata K, Komatsu T, Tanimoto T, Nukata Y, Tanabe F, Akita K, Torigoe K, Okura T, Fukuda S. A novel costimulatory factor for gamma interferon induction found in the livers of mice causes endotoxic shock.  Infect Immun. 1995;  63 3966-3972
• 21 Okamura H, Tsutsi H, Komatsu T, Yutsudo M, Hakura A, Tanimoto T, Torigoe K, Okura T, Nukada Y, Hattori K. Cloning of a new cytokine that induces IFN-gamma production by T cells [see comments].  Nature. 1995;  378 88-91
• 22 Ostrowski K, Hermann C, Bangash A, Schjerling P, Nielsen J N, Pedersen B K. A trauma-like elevation of plasma cytokines in humans in response to treadmill running.  J Physiol. 1998;  513 889-894
• 23 Ostrowski K, Rohde T, Asp S, Schjerling P, Pedersen B K. Pro- and anti-inflammatory cytokine balance in strenuous exercise in humans.  J Physiol. 1999;  515 287-291
• 24 Ostrowski K, Rohde T, Zacho M, Asp S, Pedersen B K. Evidence that interleukin-6 is produced in human skeletal muscle during prolonged running.  J Physiol. 1998;  508 949-953
• 25 Shepard R J, Shek P N. Impact of physical activity and sport on the immune system.  Rev Environ Health. 1996;  11 133-147
• 26 Shephard R J, Shek P N. Potential impact of physical activity and sport on the immune system - a brief review.  Br J Sports Med. 1994;  28 247-255
• 27 Stuyt R J, Netea M G, Verschueren I, Fantuzzi G, Dinarello C A, Van der Meer J W, Kullberg B J. Role of interleukin-18 in host defense against disseminated Candida albicans infection.  Infect Immun. 2002;  70 3284-3286
• 28 Suzuki K, Nakaji S, Yamada M, Totsuka M, Sato K, Sugawara K. Systemic inflammatory response to exhaustive exercise. Cytokine kinetics.  Exerc Immunol Rev. 2002;  8 6-48
• 29 Takeda K, Tsutsui H, Yoshimoto T, Adachi O, Yoshida N, Kishimoto T, Okamura H, Nakanishi K, Akira S. Defective NK cell activity and Th1 response in IL-18-deficient mice.  Immunity. 1998;  8 383-390
• 30 Tsutsui H, Matsui K, Kawada N, Hyodo Y, Hayashi N, Okamura H, Higashino K, Nakanishi K. IL-18 accounts for both TNF-alpha- and Fas ligand-mediated hepatotoxic pathways in endotoxin-induced liver injury in mice.  J Immunol. 1997;  159 3961-3967
• 31 Tsutsui H, Nakanishi K, Matsui K, Higashino K, Okamura H, Miyazawa Y, Kaneda K. IFN-gamma-inducing factor up-regulates Fas ligand-mediated cytotoxic activity of murine natural killer cell clones.  J Immunol. 1996;  157 3967-3973
• 32 Ushio S, Namba M, Okura T, Hattori K, Nukada Y, Akita K, Tanabe F, Konishi K, Micallef M, Fujii M, Torigoe K, Tanimoto T, Fukuda S, Ikeda M, Okamura H, Kurimoto M. Cloning of the cDNA for human IFN-gamma-inducing factor, expression in Escherichia coli, and studies on the biologic activities of the protein.  J Immunol. 1996;  156 4274-4279
• 33 Weijer S, Sewnath M E, de Vos A F, Florquin S, van der S K, Gouma D J, Takeda K, Akira S, van der Poll T. Interleukin-18 facilitates the early antimicrobial host response to Escherichia coli peritonitis.  Infect Immun. 2003;  71 5488-5497

1 Both authors contributed equally.