Exhaustive exercise reduces TNF-α and IFN-α production in response to R-848 via toll-like receptor 7 in mice

Abstract

Stressful exercise results in temporary immune depression. However, the impact of exercise on the immune responses via toll-like receptor (TLR) 7, which recognizes the common viral genomic feature, single-stranded RNA, remains unclear. To clarify the effect of stressful exercise on immune function in response to viral infection, we measured the changes in the plasma concentration of tumor necrosis factor (TNF)-α and interferon (IFN)-α, which are induced downstream from the TLR-ligand interaction, in exhaustive-exercised mice immediately after treatment with the imidazoquinoline R-848, which can bind to and activate TLR7. Both exhaustive-exercised (EX) and non-exercised (N-EX) male C3H/HeN mice were injected with R-848 (5 mg kg(-1)), and blood samples were collected. In addition, RAW264 cells, which are mouse macrophage cells, were cultured 30 min after epinephrine (10 μM) or norepinephrine (10 μM) treatments, and were then stimulated with R-848 (10 μg ml(-1)). In addition, the effect of propranolol (10 mg kg(-1)) as blockade of β-adrenergic receptors on R-848-induced TNF-α and IFN-α production in the exercised mice was examined. Both the TNF-α and IFN-α concentrations in the plasma of EX were significantly lower than those in the plasma of N-EX after R-848 injection (P < 0.05 and P < 0.01, respectively), although the R-848 treatment increased the plasma TNF-α and IFN-α concentrations in both groups (P < 0.01, respectively). The R-848-induced TNF-α production in RAW264 cells was significantly inhibited by epinephrine and norepinephrine pre-treatment, although IFN-α was not detected. The propranolol treatment completely inhibited exercise-induced TNF-α and IFN-α suppression in response to R-848 in the mice. These data suggest that EX induces a reduction in TNF-α and IFN-α production in response to R-848, and that these phenomena might be regulated by an exercise-induced elevation of the systemic catecholamines.

Physical and Immunological Aspects of Exercise in Chronic Diseases

“…Further, intense aerobic treadmill exercise increases pro-TNF-alpha and anti-IL-10 and pro-apoptotic protein (caspase 3), indicating an overall anti-inflammatory effect as a result of wheel running in healthy mice [46]. Likewise, exhaustive exercise reduces TNF-alpha and IFN-alpha concentrations and this reduction is via TLR-7 and elevation of systemic catecholamines [47]. Further, hepatic inflammation and fibrosis is reduced by reduction of TNF-alpha, macrophage infiltration and tissue inhibitor of matrix metalloproteinase-1 mRNA [48].…”

Interferon-beta, but not tumor necrosis factor-alpha, production in response to poly I:C is maintained despite exhaustive exercise in mice

“…This is, to our knowledge, the first study to demonstrate that IFN-b production in response to poly I:C is maintained, even though the mice are subjected to exhaustive exercise stress. A previous study showed that exhaustive exercise inhibited INF-a production in mice when the mice were treated by R-848 as activator of TLR7 [7]. A difference function between poly I:C/TLR3 and R-848/TLR7 might have occurred via a [11,12] despite viral ssRNA binding to TLR7 [10].…”

“…One group contained exhaustive exercising mice (EX, n = 12), and the other group contained non-exercising mice (N-EX, n = 11). The EX mice were run on a treadmill to exhaustion, and N-EX mice were kept at rest [4,7]. Mean time to exhaustion for EX mice was 65 ± 2 min.…”

“…In addition, it has been reported that exercise stress might be associated with increased susceptibility to viral infections [5,6]. However, changes in pathogen-induced type I interferons (IFN-a/b), which are very important in anti-virus response, after severe exercise are little known, although we reported that exhaustive exercise induced depression of IFN-a against injection of imidazoquinoline resiquimod (R-848), a ligand of the toll-like receptor (TLR)7 which responds to single-stranded (ss) RNA viruses to trigger IFN production in mice [7].…”

The suppression of tumor necrosis factor-alpha production in response to pathogen stimulation by strenuous exercise and underlying mechanisms

“…Strenuous exercise-induced TNF-α suppression in plasma is observed following stimulation with PGN/TLR2, poly I:C/TLR3 75) , R-848/TLR7/8 76) and CpG DNA/TLR9 (Fig. 6).…”