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1 Department of Cellular and Molecular Physiology, Penn State University College of Medicine, Hershey, PA, USA
* To whom correspondence should be addressed. E-mail: rfrost{at}psu.edu.
Interleukin-6 (IL-6) is a major inflammatory cytokine that plays a central role in coordinating the acute phase response to trauma, injury and infection in vivo. Although IL-6 is synthesized predominantly by macrophages and lymphocytes skeletal muscle is a newly recognized source of this cytokine. IL-6 from muscle spills into the circulation and blood borne IL-6 can be elevated greater than 100-fold due to exercise and injury. The purpose of the present study was to determine whether inflammatory stimuli, such as lipopolysaccharide (LPS), tumor necrosis factor-
(TNF), and IL-1
could increase IL-6 expression in skeletal muscle and C2C12 myoblasts. Secondly, we investigated the role of MAP kinases, and the Jun N-terminal kinase (JNK) in particular as a mediator of this response. Intraperitoneal injection of LPS in mice increased the circulating concentration of IL-6 from undetectable levels to 4 ng/ml. LPS also increased IL-6 mRNA 100- fold in mouse fast-twitch skeletal muscle. Addition of LPS, IL-1, or TNF directly to C2C12 myoblasts increased IL-6 protein (6- to 8-fold) and IL-6 mRNA (5- to 10- fold). The response to all three stimuli was completely blocked by the JNK inhibitor SP600125, but not as effectively by other MAP kinase inhibitors. SP600125 blocked LPS-stimulated IL-6 synthesis dose-dependently at both the RNA and protein level. SP600125 was as effective as the synthetic glucocorticoid dexamethasone at inhibiting IL-6 expression. SP600125 inhibited IL-6 synthesis when added to cells up to 60 minutes after LPS stimulation but its inhibitory effect waned with time. LPS stimulated IL-6 mRNA in both myoblasts and myotubes but myoblasts showed a proportionally greater LPS-induced increase in IL-6 protein expression compared to myotubes. SP600125 and the proteasomal inhibitor MG132 blocked LPS-induced degradation of I kappa B-/
, and LPS-stimulated expression of I kappa B- mRNA. Yet, only SP600125 and not MG132 blocked LPS-induced IL-6 mRNA expression. This suggests that IL-6 gene expression is a downstream target of JNK in C2C12 myoblasts.
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