Purpose: Currently, it is unclear how chronic exercise affects immunity. Mitogen-activated protein kinase (MAPK) mediates the production of proinflammatory cytokines, whereas MAPK phosphatase-1 (MKP-1) plays an essential role in intracellular homeostasis by negatively regulating macrophage MAPK activation. We hypothesized that chronic exercise might upregulate macrophage MKP-1 and thus prevent excessive inflammatory responses.
Methods: To verify this hypothesis, we compared the basal immune status and lipopolysaccharide (LPS)-evoked immune responses between sedentary and 8-wk treadmill exercise-trained male C57BL/6 mice.
Results: Although the basal levels of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) were undetectable in the serum of both groups, the exercised mice showed the following immune adaptations in vivo: (i) higher basal MKP-1 mRNA level in peritoneal macrophages, (ii) lower basal p38 MAPK activity and enhanced MKP-1 immunostaining in macrophages, and (iii) lower serum levels of IL-6 and TNF-α and less leukocyte infiltration into peritoneal cavity after systemic administration of LPS when compared with sedentary controls. In addition, when peritoneal macrophages isolated from exercised mice were exposed to LPS in vitro, they showed (i) accelerated MKP-1 protein expression, (ii) reduced p38 MAPK activity, and (iii) reduced cytokine secretion of IL-6, TNF-α, and monocyte chemotactic protein-1. Finally, 2 months of deconditioning completely reversed the exercise-enhanced basal MKP-1 immunostaining in macrophages and the exercise-suppressed cytokine secretion under LPS-evoked conditions.
Conclusions: Exercise training upregulated basal macrophage MKP-1 expression, accelerated LPS-evoked MKP-1 up-regulation, and affected LPS-evoked immune responses in mice.
1Institute of Basic Medical Sciences, National Cheng Kung University Medical College, Tainan, TAIWAN; and 2Department of Physiology, National Cheng Kung University Medical College, Tainan, TAIWAN
Address for correspondence: Chauying J. Jen, Ph.D., Department of Physiology, National Cheng Kung, University Medical College, Tainan, 701 Taiwan; E-mail: email@example.com.
Submitted for publication December 2009.
Accepted for publication April 2010.
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Exercise is known to affect immunity; it is the mechanisms that are unclear. Generally speaking, chronic exercise with moderate intensity is beneficial to patients with immune alteration-associated diseases, such as tumor metastasis (9), acquired immunodeficiency syndrome (23), and rheumatoid arthritis (24). In animal studies, exercise training also exerts significant effects on immunity, i.e., higher efficiency in clearing tumor cells (18), elevated phagocytic capacity in macrophages (6), improved resistance to viral infection (19), and attenuated airway inflammation (25). Although these studies support the notion that regular exercise has benefits on immune system, they rarely address the possible underlying mechanisms.
Mitogen-activated protein kinases (MAPK) are a group of serine/threonine protein kinases including ERK, JNK, and p38 subfamilies. They play important roles in various cellular functions, including differentiation, proliferation, stress responses, apoptosis, and immune response (7). Dysregulation of MAPK has been implicated in the pathogenesis of many diseases, such as septic shock, arthritis, diabetes, and atherosclerosis (8,13,15,28). Because p38 kinase inhibitors suppress the expression of inflammatory mediators, they have been used in human or animal studies to treat septic shock, arthritis, and ischemia (20). MAPK phosphatase-1 (MKP-1) is an endogenous suppressor of the MAPK-activated pathways (33). It accelerates p38 MAPK inactivation and switches off the production of TNF-α and IL-6 (2). Recent studies have shown that lack of MKP-1 leads to prolonged p38 MAPK activation and uncontrolled production of proinflammatory cytokines after lipopolysaccharide (LPS) challenge (3,12,29,37). Moreover, animals deficient in MKP-1 are more sensitive to type II collagen-induced arthritis (29). Therefore, MKP-1 plays a critical negative regulator role in innate responses to pathogen insult.
On the basis of the human microarray data obtained from peripheral blood mononuclear cells, DUSP1, the gene coded for MKP-1, is highly upregulated by acute exercise (5). Interestingly, our preliminary study indicated that the basal human leukocyte DUSP1 mRNA level was also elevated by exercise training (data not shown). Because MKP-1 suppresses LPS-evoked p38 MAPK activation and cytokine production (3,12,29,37), it is plausible to assume that chronic exercise reduces excessive inflammatory responses by upregulating MKP-1 in leukocytes. In this study, we used male C57BL/6 mice to evaluate the effects of 8-wk treadmill exercise training on their basal levels of macrophage MKP-1 and phospho-p38 MAPK and the LPS-evoked immune responses in vivo or in vitro. Moreover, we also tested whether the exercise effects would diminish or not after 2 months of deconditioning.
This study was conducted in conformity with the policy statement of the American College of Sports Medicine on research with experimental animals. The animal research protocol had been approved by the review committee in National Cheng Kung University (IACUC approved number 95049). Male 7-wk-old C57BL/6NCrj mice were purchased from the National Cheng Kung University Animal Center, and they were housed in an environmentally controlled room, four per cage, with a temperature of 25°C ± 1°C, 12-h light, and 12-h dark. Chow and water were available ad libitum. Mice were divided randomly into sedentary and exercise groups. For each experiment, we used the same batch of mice, about half for each group.
It has been shown that the oxygen consumption of small rodents running on the treadmill can be predicted by their running speed (10). On the basis of our previous study (22), the following exercise protocols were used for mice to achieve moderate exercise (approximately 60% of maximal oxygen consumption). At the beginning, mice ran on a treadmill (Model T510E; Diagnostic and Research Instruments Co., Taoyuan, Taiwan) at a speed of 9 m·min−1 for 10 min during the 1-wk familiarization period. After familiarization, mice in the exercise group were trained for 60 min·d−1, 5 d·wk−1 at the speed of 10 m·min−1 for the first 4 wk and 13 m·min−1 for the last 4 wk. Mice in the control group were placed on the treadmill for 10 min·d−1 without receiving any exercise training, 5 d·wk−1 for 8 wk. Electric shocks were never applied to animals to avoid possible stress effects. We previously showed that a similar exercise intensity would induce a transient elevation of serum corticosterone (22). This corticosterone elevation diminished within 1 h and remained at a low level afterward, indicating that the stress effects were minimal. Forty-eight hours after training, mice were sacrificed by CO2 euthanasia to collect the peripheral leukocytes, serum, and peritoneal immune cells.
RNA extraction and quantitative real-time polymerase chain reaction (PCR) analysis.
Total cellular RNA was extracted from either total peripheral leukocytes or peritoneal macrophages using the RNeasy Midi Kit (Qiagen, Venlo, The Netherlands) according to the manufacturer's recommendations. For the synthesis of first-strand complementary DNA, 1 μg of total RNA was incubated with 200 U of SuperScript II Reverse Transcriptase (Invitrogen, Carlsbad, CA) and 200 ng of random primers (Protech Technology, Taipei, Taiwan) at 25°C for 10 min, followed by 42°C for 50 min and 70°C for another 15 min. Real-time PCR was performed by LightCycler FastStart DNA Master SYBR Green I (Roche Diagnostics Ltd., Lewes, UK) for specimens and diluted standards. A serial dilution of purified DNA was used for real-time PCR calibration, and PCR-grade H2O was used as the negative control. The sequences of primers used in this study are as follows: mouse GAPDH, 5′-CATGGCCTTCCGTGTTC-3′ (forward) and 5′-CCTGGTCCTCAGTGTAGC-3′ (reverse); mouse MKP-1, 5′-GATCAACGTCTCAGCCAA-3′ (forward) and 5′-CCTGGCAATGAACAAACAC-3′ (reverse). The PCR began with denaturation at 95°C for 7 min, followed by 60 cycles of denaturation at 95°C for 5 s, annealing at 60°C for 5 s, and extension at 72°C for 10 s. Samples were measured in duplicates, and the percentages of coefficient of variation were <5%. The MKP-1 expression value was normalized against its own internal control GAPDH. The averaged MKP-1 level in the exercise group was subsequently normalized against that in the sedentary group.
Isolation and characterization of peritoneal cells after LPS treatment in vivo.
Two days after the last run, mice were intraperitoneally (i.p.) injected with LPS (Escherichia coli O127:B8; Sigma-Aldrich, St. Louis, MO; 5 mg·kg−1 body weight). Mice were sacrificed 1, 2, 3, or 24 h after LPS treatment. Peritoneal lavage was collected, and the cell concentration was determined by using a hemacytometer. Peritoneal fluid was then transferred to a cytocentrifuge container to prepare a cell smear for differential leukocyte counts (400 cells for each specimen). Peritoneal macrophages were enriched by plastic adherence for further biochemical analysis.
Isolation of peritoneal macrophages for LPS treatment in vitro.
To boost the number of peritoneal macrophages, mice were i.p. injected with 2 mL of 3% Brewer thioglycollate medium (Sigma-Aldrich) at 2 h after the last run. Peritoneal macrophages were harvested 2 d later by peritoneal lavage in RPMI-1640 medium (Gibco BRL, Grand Island, NY) and were enriched by plastic adherence. Differential cell counts under a microscope indicated that neither total leukocytes nor macrophage percentages were significantly different between groups. The macrophages were cultured overnight in RPMI-1640 medium containing 5% heat-inactivated fetal bovine serum (FBS) (Hyclone, Logan, UT) and were subsequently stimulated with 100 ng·mL−1 of LPS.
Protein extraction and Western blot analysis.
Total protein extraction was performed by using protein extraction buffer (Pierce, Biotechnology, Rockford, IL) containing complete protease inhibitor cocktail (Roche). Protein samples were separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and were transferred to a polyvinylidene fluoride (PVDF) membrane (PerkinElmer Life Science, Boston, MA). After blocking, the membrane was incubated with primary antibodies. Polyclonal antibodies specific for GAPDH (FL-335) and MKP-1 (C-19) were purchased from Santa Cruz Biotechnology (Santa Cruz, CA); those for phospho-p38 (Thr180/Tyr182) and p38 MAPK were purchased from Cell Signaling Technology (Beverly, MA). Finally, horseradish peroxidase-conjugated secondary antibody, i.e., goat antirabbit IgG (Cell Signaling Technology), was used, and this was followed by an ECL Western blot detection reagent (Millipore, Billerica, MA) or a Femto-ECL reagent (Pierce).
Concentrations of TNF-α, IL-6, and monocyte chemotactic protein-1 (MCP-1) in cell culture medium or serum were detected by using Duoset ELISA analysis (R&D Systems, Minneapolis, MN) according to the manufacturer's instructions. Serum samples were diluted 1:100 or 1:10 for the ELISA, whereas cell culture media were not diluted before assay. Specimens and standard solutions were diluted, if necessary, with 1% bovine serum albumin (BSA) (Sigma-Aldrich) in phosphered buffered saline (PBS). Samples were measured in triplicates, and the percentage CV were <15%.
Immunofluorescence staining of macrophage MKP-1.
Macrophages were placed onto 20-mm-diameter cover glasses. After cytospin, samples were fixed with cold acetone-methanol (1:1) for 10 min at −20°C, blocked with 3% FBS for 30 min in PBS, and then incubated with the anti-MKP-1 antibody (1:100) in 1% FBS at 4°C overnight. After PBS washing, samples were incubated with Alexa Fluor 488-conjugated goat antirabbit IgG (1:200; Molecular Probes, Eugene, OR) in 1% FBS at room temperature for 1 h. In addition, nuclei were stained by 1 μg·mL−1 of propidium iodide (Sigma-Aldrich) at room temperature for 30 min. After washing, slides were mounted with an antifade solution (Vectashield; Vector Laboratories, Burlingame, CA) and were viewed on a fluorescence microscope.
The between-group comparisons of single-point measurements (MKP-1 mRNA or phospho-p38 MAPK) were carried out using unpaired Student's t-test. The time course studies of LPS-induced MKP-1 and phospho-p38 protein expression or LPS-induced cytokine secretion were analyzed using two-way ANOVA followed by Bonferroni posttests. All tests were performed using PRISM software (GraphPad, San Diego, CA). Data were expressed as mean ± SEM. Significant difference between groups was expressed as follows: *P < 0.05, **P < 0.01, ***P < 0.001.
To test our hypothesis, we first investigated whether chronic exercise would upregulate the expression of MKP-1 in murine peritoneal macrophages or not. Eight weeks of moderate exercise training in mice significantly elevated peritoneal macrophage MKP-1 mRNA level (Fig. 1A) and MKP-1 immunostaining (see Fig. S1, Supplemental Digital Content, Effects of exercise training on the MKP-1 staining in unstimulated macrophages, http://links.lww.com/MSS/A29). Moreover, the basal level of phospho-p38 MAPK in peritoneal macrophages was drastically reduced by exercise training (Fig. 1B), indicating an elevated basal MKP-1 activity in macrophages isolated from exercised animals.
We further examined whether the LPS-evoked cytokine production kinetics in vivo could be modulated by exercise training or not. Before LPS administration, neither sedentary nor trained group showed any detectable amounts of TNF-α or IL-6 in the serum (Fig. 2A). Although the LPS administration induced significant elevations of these two cytokines in both groups, the LPS-evoked cytokine production was much retarded by exercise training. These results supported the notion that exercise training negatively regulated LPS-evoked cytokine production.
A recent study has demonstrated that MKP-1 suppresses the induction of MCP-1 (17), which plays a key role in attracting monocytes and neutrophils. Along with the presence of chemokines, the vascular permeability would increase to help immune cells infiltrate into the inflammatory site. We thus examined the effects of exercise training on LPS-evoked immune cell infiltration into the peritoneal cavity. It seemed that LPS administration induced a transient immune cell infiltration, which happened earlier and lasted longer in the sedentary control group than that in the exercise-trained group (Fig. 2B). The kinetic changes of infiltrated cells basically followed that of macrophages, the major component in the peritoneal lavage. As a comparison, the neutrophils continuously infiltrated into the peritoneal cavity for at least 24 h in the sedentary group, whereas their infiltration ceased at 2 h in the exercise group. Lymphocytes accounted only approximately 1% of total infiltrated immune cells and did not differ between exercised and sedentary groups (data not shown). These results demonstrated that exercise-trained mice were more resistant to the LPS stimulation in vivo.
We further examined the effects of exercise on macrophages that were stimulated by LPS in vitro. To obtain sufficient amounts of macrophages for immunoblotting experiments, peritoneal macrophages were collected 2 d after i.p. injection of thioglycollate. The isolated macrophages were then treated with 100 ng·mL−1 of LPS in vitro. LPS induced a transient MKP-1 protein expression that happened earlier in macrophages from exercised mice than that in those from controls (Fig. 3A). Consistently, the LPS-induced p38 MAPK activation was relatively suppressed in macrophages isolated from exercised animals (Fig. 3B). Furthermore, the LPS-induced production of TNF-α and IL-6 in these macrophages was relatively mild, as indicated by reduced amounts of cytokines in the culture supernatant (Figs. 4, A and B). To explore the possible factor associated with leukocyte infiltration, we also measured the supernatant level of MCP-1. The LPS-evoked secretion of this monocyte chemotactic protein was reduced in the exercise group as well (Fig. 4C).
Whether deconditioning effects would happen to the exercise-altered immune function is an intriguing issue. Our immunostaining results indicated that, in peritoneal macrophages, (i) the basal MKP-1 expression was weakly detectable only in the exercise group, (ii) the LPS-evoked MKP-1 expression in vitro was accelerated by exercise training, and (iii) deconditioning rendered the basal MKP-1 level undetectable and rendered the time course of LPS-induced MKP-1 expression similar to that in the age-matched sedentary control group (Fig. 5A). In addition, the deconditioned and sedentary groups behaved similarly in their in vitro LPS-evoked cytokine production (Fig. 5B). Taken together, these results demonstrated that deconditioning was able to abolish at least some effects of exercise training, i.e., the elevation of basal MKP-1 level, the acceleration of LPS-evoked MKP-1 induction, and the suppression of LPS-evoked cytokine production.
This study is the first to demonstrate that exercise training increases the basal MKP-1 expression/activity in peritoneal macrophages and accelerates their MKP-1 response when subjected to LPS challenge. In the basal state, exercise-trained animals were in a lower inflammatory state compared with the sedentary animals, and they could rapidly recover from the LPS-evoked inflammatory state. Finally, the effects of exercise training on immunity were lost after a period of deconditioning. Our results support the notion that MKP-1 plays a role in exercise training-mediated immune adaptation.
How exercise affects immunity is an important issue under active research. In this study, we discovered an adaptive response of the immune system to chronic exercise, i.e., mice after 8 wk of exercise training showed a higher basal MKP-1 expression in immune cells, and thus, they situated in a relatively anti-inflammatory state compared with the sedentary controls. Exercise effects can be classified into acute and chronic effects. Acute effects are examined immediately after or soon after a single bout of exercise, whereas chronic effects are typically monitored under resting conditions a few days after cessation of exercise training. We have used rodent models to show that acute severe exercise (>80% of maximal oxygen consumption) induces thymocyte apoptosis and enhances the phagocytotic capacity in bronchoalveolar macrophages (BAM) (31,32). Interestingly, IL-6, an interleukin produced by skeletal muscle during exercise, has been proposed to be a mediator for the anti-inflammatory effects of exercise (26). However, the exercise-evoked release of IL-6 is an acute and transient effect of exercise, i.e., the serum level of IL-6 returns to resting value immediately after exercise. Moreover, such an exercise effect becomes blunted with repeated bouts of exercise (11). In our hands, without LPS administration, neither sedentary nor exercise-trained mice showed any detectable amounts of IL-6 in their sera (Fig. 2A).
How exercise modulates the expression of MKP-1 is an intriguing question. A human microarray study has revealed that acute severe exercise (>80% peak O2 uptake) altered the expression of many genes, including DUSP1 (the gene encoding MKP-1), in the peripheral blood mononuclear cells (5). However, the expression level of DUSP1 (along with many other genes) returns to the basal level after 60 min of recovery. Because our preliminary study indicated that the human leukocyte basal DUSP1 level was also elevated by exercise training (data not shown), it seems that long-term exercise training could convert the transient MKP-1 elevation after each bout of exercise into a higher basal level of MKP-1, which would alter the day-to-day immune responses.
Exercise is accompanied with transient elevations of various stress hormones, particularly corticosteroids (cortisol in humans and corticosterone in rodents). In our hands, acute moderate exercise transiently increases the plasma corticosterone level, which returns to the basal level after 1 h of resting (16). Corticosteroids bind to cytoplasmic glucocorticoid receptors, and the complex subsequently moves into the nucleus and binds to glucocorticoid response element to enhance the expression of many stress-related genes. It has been reported that glucocorticoids induce the sustained expression of MKP-1 to block the activation of p38 MAPK along with the downstream production of TNF-α and IL-6 (27). Moreover, glucocorticoid receptor-deficient macrophages are resistant to dexamethasone-dependent cytokine inhibition, and dexamethasone cannot prevent excessive immune response in MKP-1-deficient mice (1,34). On the basis of these observations, we hypothesize that exercise training may increase MKP-1 expression via corticosteroid stimulation. Whether and how repeated transient elevations of serum corticosterone level in mice induce higher basal MKP-1 expression remain to be investigated.
Alternatively, exercise training may increase MKP-1 expression via elevated flow shear stress in the vasculature. It is well known that lack of regular exercise is one of the major risk factors for various cardiovascular diseases, such as atherosclerosis, hypertension, myocardial infarction, and stroke. Atherosclerosis is associated with chronic inflammation, which often happens at arterial sites with disturbed blood flow pattern (14). Moreover, because the flow shear stress has anti-inflammatory effects on vascular cells, the atheroprotective effects of exercise have been attributed to the elevated blood flow (4). It has been hypothesized that steady laminar flow inhibits cytokine-mediated activation of MAPK in endothelial cells (35). In fact, some studies have reported that MKP-1 is elevated by shear stress in cultured vascular smooth muscle cells and endothelial cells (36). It would be interesting to know whether some kind of flow-related mechanism also applies to the circulating immune cells.
Macrophages from prototypical TH1 strains (e.g., C57BL/6) and TH2 strains (e.g., BALB/c) are classified as M-1 and M-2 phenotypes. Because only a minor part of M-2 macrophage activation involves the MAPK pathway-dependent secretion of cytokines (30), whether our major discoveries from C57BL/6 mice studies can be applied to BALB/c mice or to other strains has to be experimentally verified. In our previous study, M-1 and M-2 BAM show different phagocytic responses under resting and acute exercise conditions (31). That is, the phagocytic capacity in M-1 BAM is higher than that in M-2 BAM at rest, and severe exercise only augments this functional parameter in M-2 BAM.
Several recent studies have suggested that higher MKP-1 and lower p-p38 MAPK expression may contribute to the anti-inflammatory effects (20,21,27,36). Drugs stimulating MKP-1 protein expression have been used to attenuate the progression of various immune-related diseases, such as airflow obstruction (21), airway inflammation (27), and atherosclerosis (36). In addition, drugs acting as p38 MAPK inhibitors have been used in preclinical and clinical studies of septic shock, arthritis, and ischemia (20). Our results suggest that exercise training at moderate intensity may be used as a potential therapeutic intervention for treating inflammatory diseases.
This study was supported by grants from the National Science Council, Taiwan (NSC 96-2320-B-006-003 and NSC 98-2320-B-006-028-MY3).
Results of the present study do not constitute endorsement by the American College of Sports Medicine.
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CYTOKINE; DECONDITIONING; IMMUNITY; INFLAMMATION; LPS; MAPK
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