Eric R Szelenyi1, Maria L Urso. 1. U.S. Army Research Institute of Environmental Medicine, 42 Kansas Street, Building 42, Natick, Massachusetts 01760, USA.
Abstract
INTRODUCTION: The coupling and timing of pro- and anti-inflammatory processes in skeletal muscle injury is poorly understood. We investigated the temporal response and regulated processes of extracellular signal-regulated kinases 1 and 2 (ERK1/2), p38, and IkappaB kinase (IKK) α/β signaling pathways after traumatic injury. METHODS: Traumatic freeze injury was delivered to the tibialis anterior (TA) muscle in C57BL/6J mice, and injured and uninjured TA muscles were analyzed 3-72 h into the recovery period. RESULTS: Significant increases in pro-inflammatory cytokine transcription accompanied IKKβ phosphorylation, robust ERK pathway activation, and reduced heat shock protein (Hsp) protein expression at 3-24 h. At 24 h, ERK activation was abolished concomitantly with a significant increase in mitogen-activated protein kinase phosphatase-1 (MKP-1). After 24 h, cytokine transcription along with ERK1/2 and IKKβ phosphorylation remained suppressed, whereas Hsp protein expression rose to significant levels by 72 h and associated with IKKβ. CONCLUSIONS: Results indicate a bimodal regulation of ERK1/2 in acute inflammation in which it is supportive from 3 to 24 h, and suppressive from 24 to 72 h.
INTRODUCTION: The coupling and timing of pro- and anti-inflammatory processes in skeletal muscle injury is poorly understood. We investigated the temporal response and regulated processes of extracellular signal-regulated kinases 1 and 2 (ERK1/2), p38, and IkappaB kinase (IKK) α/β signaling pathways after traumatic injury. METHODS:Traumatic freeze injury was delivered to the tibialis anterior (TA) muscle in C57BL/6J mice, and injured and uninjured TA muscles were analyzed 3-72 h into the recovery period. RESULTS: Significant increases in pro-inflammatory cytokine transcription accompanied IKKβ phosphorylation, robust ERK pathway activation, and reduced heat shock protein (Hsp) protein expression at 3-24 h. At 24 h, ERK activation was abolished concomitantly with a significant increase in mitogen-activated protein kinase phosphatase-1 (MKP-1). After 24 h, cytokine transcription along with ERK1/2 and IKKβ phosphorylation remained suppressed, whereas Hsp protein expression rose to significant levels by 72 h and associated with IKKβ. CONCLUSIONS: Results indicate a bimodal regulation of ERK1/2 in acute inflammation in which it is supportive from 3 to 24 h, and suppressive from 24 to 72 h.
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