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FJ
EXPRESS SUMMARY ARTICLE The Full-length version of this article is also available, published online July 18, 2005 as doi:10.1096/fj.04-3063fje. |
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,
* Department of Sports Medicine, Friedrich-Schiller-University Jena, Germany;
SIRS-Lab GmbH, Jena, Germany;
Department for Anesthesiology and Intensive Care Medicine, University Hospital, Jena, Germany; and
School of Chemical Sciences and Pharmacy, University of East Anglia, Norwich, UK
1Correspondence: T. H., Department of Sports Medicine Friedrich-Schiller-University Jena, Wöllnitzerstr. 42, Jena 07749, Germany. E-mail: thomas.hilberg{at}uni-jena.de; H.-P. D., SIRS-Lab GmbH, Winzerlaer Str. 2A, Jena 07745, Germany, and School of Chemical Sciences and Pharmacy, University of East Anglia, Norwich NR4 7TJ, UK. E-mail: h-p.deigner{at}uea.ac.uk
SPECIFIC AIMS
This study was performed to analyze transcriptional responses to strenuous standardized and prolonged physical stress in the blood of healthy individuals. The emphasis was placed on exercise-induced events with immunological relevance, in particular in the context of bronchoconstriction.
PRINCIPAL FINDINGS
1. Exercise-induced stress (treadmill exercise with 90% of the individual anaerobic threshold for 90 min) resulted in changes of physiological and immunological parameters as well as blood cell counts in healthy trained subjects (Table 1
)
Time-dependent alterations (2 and 6 h after exercise) in the expression pattern of leukocytes were analyzed by DNA microarrays after exercise stress test and provoked changes in the expression of 433 gene activities. These could be grouped into six clusters depending on the progression of their activities, one group is depicted in Table 2
c (only the most statistically relevant changes in gene transcription are shown; mean 
–0.3 or 
0.3, P<0.05).
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2. The most prominent feature was an enhanced transcription of both genes (ALOX5 and ALOX5AP) coding for 5-lipoxygenase and 5-lipoxygenase activating protein
As a consequence, an enhanced plasma level of leukotriene B4 (LTB4) and leukotriene C4 (LTC4) was found.
3. Subsequent to the microarray investigations, we verified a set of gene activities (ALOX5AP, S100A11 having a significant change in expression and IL17B being unchanged) by an independent method using real-time PCR
The resulting data were normalized to GADPH, which was chosen for normalization as its expression rate is among the most stable in leukocytes and was unchanged in our experimental settings. Our data indicate a close correlation between microarray and real-time PCR data for all three assayed genes.
CONCLUSIONS AND SIGNIFICANCE
In this study, an exercise test has been carried out to examine stress-induced immunological signaling and to elucidate the resultant pattern of immunological changes in response to physiological stress. On the basis of this stress test, a comprehensive approach of gene expression analysis by microarray technique and validation of these results via real-time PCR was used to discover relations between immunological signaling pathways after physical stress. The meaning and potential of the results of this study can be emphasized by the following central finding.
Exercise-induced bronchoconstriction and asthma-like symptoms are common health problems affecting the general population as well as athletes, in particular with the highest prevalence, in well trained elite athletes. In 10–50% of elite athletes and 12% of school children, an exercise-induced bronchospasm (EIB) and/or exercise induced asthma (EIA) occur during and most often after exercise. Although numerous studies have been published focusing on the immunological reaction, relevant mechanisms have only been revealed fragmentarily. Evidence suggests that histamine, prostanoids, and leukotrienes are likely mediators for this response. Moreover, leukotrienes are increased after exercise; in fact, it is well established that exercise stimulates arachidonic acid metabolism therefore increasing LTB4 and LTC4-levels and all of them are known to be involved in the induction of asthma. Arm et al. have shown that 3 and 6 h after exercise-induced asthma, PMN isolated from asthmatic subjects and stimulated in vitro demonstrate an increase up to 12-fold in the production of immunoreactive LTB4 as compared with PMN isolated before exercise. We found via mircoarray analysis that the transcription of 5-lipoxygenase enzyme as well as the 5-lipoxygenase activating protein is enhanced after exercise (Table 2c)
. An increased expression of both 5-lipooxygenase enzyme as well as 5-lipoxygenase activating protein mRNA have been described in the peripheral blood leukocytes of asthmatic patients compared with control subjects, suggesting a special role for transcriptional activation in the pathogenesis of asthma. Thus, we are able to provide novel insights for the molecular mechanisms underlying exercise-induced enhancement of arachidonic acid metabolism. The increased formation of the biological effector molecules leukotriene B4 and C4 during and after exercise is likely to be at least partially due to an enhanced transcription of the enzyme lipoxygenase and—which may be even of a higher biological relevance—the consequential enhanced transcription of 5-lipoxygenase activating protein. Accordingly, 5-lipoxygenase activating protein inhibitors such as MK886, may be efficient inhibitors of exercise-induced asthma as leukotriene receptor antagonists have been shown to be effective against asthma and EIA.
To our knowledge, no report has been demonstrated a link between the 5-lipoxygenase activity during exercise to altered enzyme and/or the 5-lipoxygenase activating protein transcription. There are several studies supporting functional links between oxidative stress and lipoxygenases such as 12-or 15-lipoxygenase. However, the data presented here, suggesting a significant role of the activating protein, are novel in this context.
Although the biological meaning of the observed changes in gene expression of the other more than 400 genes is not yet totally explainable, these observations could help to clarify the pattern of immunological reactions after stress. We provide evidence that the combination of an exercise model and a multiparameter approach such as microarray analyses is definitely helpful to shed light on immunological regulations.
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FOOTNOTES
To read the full text of this article, go to http://www.fasebj.org/cgi/doi/10.1096/fj.04-3063fje;
This article has been cited by other articles:
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  E. Fehrenbach Multifarious microarray-based gene expression patterns in response to exercise J Appl Physiol, January 1, 2007; 102(1): 7 - 8. [Full Text] [PDF]
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P. Buttner, S. Mosig, A. Lechtermann, H. Funke, and F. C. Mooren Exercise affects the gene expression profiles of human white blood cells J Appl Physiol, January 1, 2007; 102(1): 26 - 36. [Abstract] [Full Text] [PDF]
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