ReviewGM-CSF as a therapeutic target in inflammatory diseases
Section snippets
Production of GM-CSF
Granulocyte macrophage colony stimulating factor (GM-CSF, or CSF2) was first purified from LPS treated mouse lung-conditioned medium. It was subsequently characterised as a haemopoietic growth factor that stimulates the proliferation of myeloid cells from bone-marrow progenitors (Burgess et al., 1977). Human and mouse GM-CSF share a high level of amino acid homology (Gough et al., 1984, Lee et al., 1985), but are species-specific in terms of receptor binding (Shanafelt et al., 1991). GM-CSF can
The GM-CSF receptor
The GM-CSF receptor (CSF2R) is a heterodimer, composed of a specific ligand-binding α-chain (CSF2Rα), which binds GM-CSF with low affinity and a signal-transducing β-chain (CSF2Rβ) (Gearing et al., 1989, Hayashida et al., 1990). High affinity binding follows dimerization of both chains. For signal transduction, the cytoplasmic domains of both the α and β chain are required, but it is mainly the β chain that binds JAK2 (Hansen et al., 2008). Signalling from the CSF2R complex activates the
Too much or too little?
Abnormalities in GM-CSF production or CSF2R function have been implicated in multiple human pathologies such as RA (Bell et al., 1995), juvenile myelomonocytic leukaemia (Birnbaum et al., 2000), chronic myelomonocytic leukaemia (Ramshaw et al., 2002) and pulmonary alveolar proteinosis (PAP) (Dirksen et al., 1998, Seymour et al., 1998). Many of the features of these human conditions have been studied in mice deficient for GM-CSF or the CSF2R and mice that overexpress GM-CSF. In addition,
GM-CSF and Th17 cells
Perhaps surprisingly, GM-CSF is actually produced in high levels by T cells during inflammation (Wada et al., 1997, Ponomarev et al., 2006, Shi et al., 2006) and it has been found recently that GM-CSF is linked to the IL-23/IL-17 pathway (Campbell et al., 2011a, Codarri et al., 2011, El-Behi et al., 2011, Poppensieker et al., 2012; Van Nieuwenhuijze et al., unpublished observations). GM-CSF promoted the induction and survival of autoimmune Th17 effector cells in a CD4 T cell-mediated model of
GM-CSF autoantibodies
Intriguingly, serum GM-CSF in both mice and humans is generally present in a complex with GM-CSF autoantibodies (Uchida et al., 2009). Free GM-CSF is maintained at very low, often undetectable levels in the serum and tissues (Carraway et al., 2000, Uchida et al., 2009), but is nevertheless essential for the maintenance of some myeloid cell functions in the lungs. In humans, autoimmune PAP is characterized by high levels of auto-antibodies to GM-CSF, or the defective expression of the CSF2R (
GM-CSF inhibitors in the clinic
Conventional disease-modifying anti-rheumatic drugs (DMARDS), such as methotrexate, are routinely used alone or in combination for the treatment of RA. However, despite the beneficial effect on clinical symptoms and joint damage, DMARDS do not yield the desired outcome for some patients (Smolen et al., 2007). In the past decade, new biological therapies have been introduced in the clinic or are currently in clinical trials for RA and other inflammatory conditions, which has significantly
GM-CSF and pain
Pain is one of the main symptoms of inflammatory diseases like RA, and rated as one of the highest priorities by RA patients (Lee, 2013, Wolfe and Michaud, 2007). The relatively recent and surprising finding that functional GM-CSF receptors are present on sensory nerves has led to the investigation of GM-CSF as a mediator of pain (Schweizerhof et al., 2009). In this study, GM-CSF secreted by tumour cells was linked to signal transduction in nociceptors, and directly mediated bone tumour-induced
Concluding remarks
There are many facets to GM-CSF biology – haemopoietic growth factor, inducer of myeloid and T cell differentiation, pro-inflammatory mediator and neuromodulator. The pre-clinical data provides a strong rationale for considering GM-CSF as a potential therapeutic target for inflammatory diseases. Recent trials with specific GM-CSF or CSF2R inhibitors promise improved treatment options for patients with inflammatory conditions. Careful monitoring for potential side effects, particularly PAP,
Acknowledgements
This work was supported by The Reid Charitable Trusts, NHMRC Program Grant 1016647, NHMRC Clinical Practitioner Fellowship 1023407 (IW), NHMRC Independent Research Institute Infrastructure Support Scheme Grant (361646), and a Victorian State Government Operational Infrastructure Support grant.
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