| Summary: | Background Consensus panels regularly recommend aerobic exercise for its health‐promoting properties, due in part to presumed anti‐inflammatory effects, but many studies show no such effect, possibly related to study differences in participants, interventions, inflammatory markers, and statistical approaches. This variability makes an unequivocal determination of the anti‐inflammatory effects of aerobic training elusive. Methods and Results We conducted a randomized controlled trial of 12 weeks of aerobic exercise training or a wait list control condition followed by 4 weeks of sedentary deconditioning on lipopolysaccharide (0, 0.1, and 1.0 ng/mL)‐inducible tumor necrosis factor‐α (TNF‐α) and interleukin‐6 (IL‐6), and on toll‐like receptor 4 in 119 healthy, sedentary young adults. Aerobic capacity by cardiopulmonary exercise testing was measured at study entry (T1) and after training (T2) and deconditioning (T3). Despite a 15% increase in maximal oxygen consumption, there were no changes in inflammatory markers. Additional analyses revealed a differential longitudinal aerobic exercise training effect by lipopolysaccharide level in inducible TNF‐α (P=0.08) and IL‐6 (P=0.011), showing T1 to T2 increases rather than decreases in inducible (lipopolysaccharide 0.1, 1.0 versus 0.0 ng/mL) TNF‐α (51% increase, P=0.041) and IL‐6 (42% increase, P=0.11), and significant T2 to T3 decreases in inducible TNF‐α (54% decrease, P=0.007) and IL‐6 (55% decrease, P<0.001). There were no significant changes in either group at the 0.0 ng/mL lipopolysaccharide level for TNF‐α or IL‐6. Conclusions The failure to support the primary hypotheses and the unexpected post hoc findings of an exercise‐training–induced proinflammatory response raise questions about whether and under what conditions exercise training has anti‐inflammatory effects. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT01335737.
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