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Published Online: 1 September 2015

Regulation of Granulocyte Colony-Stimulating Factor and Its Receptor in Skeletal Muscle Is Dependent Upon the Type of Inflammatory Stimulus

Publication: Journal of Interferon & Cytokine Research
Volume 35, Issue Number 9


The cytokine granulocyte colony-stimulating factor (G-CSF) binds to its receptor (G-CSFR) to stimulate hematopoietic stem cell mobilization, myelopoiesis, and the production and activation of neutrophils. In response to exercise-induced muscle damage, G-CSF is increased in circulation and G-CSFR has recently been identified in skeletal muscle cells. While G-CSF/G-CSFR activation mediates pro- and anti-inflammatory responses, our understanding of the role and regulation in the muscle is limited. The aim of this study was to investigate, in vitro and in vivo, the role and regulation of G-CSF and G-CSFR in skeletal muscle under conditions of muscle inflammation and damage. First, C2C12 myotubes were treated with lipopolysaccharide (LPS) with and without G-CSF to determine if G-CSF modulates the inflammatory response. Second, the regulation of G-CSF and its receptor was measured following eccentric exercise-induced muscle damage and the expression levels we investigated for redox sensitivity by administering the antioxidant N-acetylcysteine (NAC). LPS stimulation of C2C12 myotubes resulted in increases in G-CSF, interleukin (IL)-6, monocyte chemoattractant protein-1 (MCP-1), and tumor necrosis factor-α (TNFα) messenger RNA (mRNA) and an increase in G-CSF, IL-6, and MCP-1 release from C2C12 myotubes. The addition of G-CSF following LPS stimulation of C2C12 myotubes increased IL-6 mRNA and cytokine release into the media, however it did not affect MCP-1 or TNFα. Following eccentric exercise-induced muscle damage in humans, G-CSF levels were either marginally increased in circulation or remain unaltered in skeletal muscle. Similarly, G-CSFR levels remained unchanged in response to damaging exercise and G-CSF/G-CSFR did not change in response to NAC. Collectively, these findings suggest that G-CSF may cooperate with IL-6 and potentially promote muscle regeneration in vitro, whereas in vivo aseptic inflammation induced by exercise did not change G-CSF and G-CSFR responses. These observations suggest that different models of inflammation produce a different G-CSF response.

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Published In

cover image Journal of Interferon & Cytokine Research
Journal of Interferon & Cytokine Research
Volume 35Issue Number 9September 2015
Pages: 710 - 719
PubMed: 26057332


Published in print: September 2015
Published online: 1 September 2015
Published ahead of print: 9 June 2015
Accepted: 27 March 2015
Received: 11 September 2014


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Craig Robert Wright
Centre for Physical Activity and Nutrition, School of Exercise and Nutrition Sciences, Deakin University, Burwood, Victoria, Australia.
Erin Louise Brown
Centre for Physical Activity and Nutrition, School of Exercise and Nutrition Sciences, Deakin University, Burwood, Victoria, Australia.
Paul A. Della Gatta
Centre for Physical Activity and Nutrition, School of Exercise and Nutrition Sciences, Deakin University, Burwood, Victoria, Australia.
Ioannis G. Fatouros
Department of Physical Education and Sport Sciences, Democritus University of Thrace, Komotini, Greece.
The Institute of Human Performance and Rehabilitation, Center for Research and Technology–Thessaly, Trikala, Greece.
Leonidas G. Karagounis
Nestlé Research Center, Nestec Ltd., Lausanne, Switzerland.
School of Physical Education and Sport Sciences, University of Thessaly, Karies, Trikala, Greece.
Gerasimos Terzis
Athletics Laboratory, School of Physical Education and Sports Science, University of Athens, Athens, Greece.
Georgios Mastorakos
Endocrine Unit, Second Department of Obstetrics and Gynecology, Athens University Medical School, Athens, Greece.
Yannis Michailidis
Department of Physical Education and Sport Sciences, Democritus University of Thrace, Komotini, Greece.
Dimitris Mandalidis
Athletics Laboratory, School of Physical Education and Sports Science, University of Athens, Athens, Greece.
Kontantinos Spengos
The 1st Department of Neurology, University of Athens, School of Medicine, Eginition Hospital, Athens, Greece.
Athanasios Chatzinikolaou
Department of Physical Education and Sport Sciences, Democritus University of Thrace, Komotini, Greece.
Spiros Methenitis
Athletics Laboratory, School of Physical Education and Sports Science, University of Athens, Athens, Greece.
Dimitrios Draganidis
Department of Physical Education and Sport Sciences, Democritus University of Thrace, Komotini, Greece.
Athanasios Z. Jamurtas
The Institute of Human Performance and Rehabilitation, Center for Research and Technology–Thessaly, Trikala, Greece.
School of Physical Education and Sport Sciences, University of Thessaly, Karies, Trikala, Greece.
Aaron Paul Russell
Centre for Physical Activity and Nutrition, School of Exercise and Nutrition Sciences, Deakin University, Burwood, Victoria, Australia.


Address correspondence to:Prof. Aaron Paul RussellCentre for Physical Activity and NutritionSchool of Exercise and Nutrition SciencesDeakin UniversityBurwood, Vic 3125Australia
E-mail: [email protected]

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