granulocyte macrophage colony - stimulating factor ( gm - csf ) is a hematopoietic growth factor which was originally recognized as a stimulator for the proliferation of granulocytes and macrophages from bone marrow precursor cells .
it has also been shown to promote the survival and activation of mature myeloid cells and therefore contributes to the maintenance of innate immune homeostasis .
recent studies suggest that gm - csf also has proinflammatory functions and plays critical roles in the development of autoimmune and inflammatory diseases , particularly in th17 driven diseases [ 3 , 4 ] .
major sources of gm - csf include activated t and b cells , monocytes / macrophages , endothelial cells , fibroblasts , and other sources such as neutrophils , eosinophils , epithelial cells , mesothelial cells , chondrocytes , paneth cells , and tumor cells [ 57 ] .
the production of gm - csf in t cells is stimulated by il-1 and il-23 in mice [ 3 , 8 ] , il-1 and il-12 in humans , and also prostaglandin e2 . in fibroblasts , endothelial cells , chondrocytes , and smooth muscle cells ,
it is stimulated by tnf- and il-1 , and in macrophage / monocytes it is stimulated by toll like receptors ( tlrs ) . in lymphocytes , the transcription factor nuclear factor of activated t cells ( nfat ) is reported to be required for the production of gm - csf [ 11 , 12 ] .
however , the production of gm - csf can be inhibited by ifn- , il-4 , il-10 , and also pharmacological agents such as cyclosporine a [ 16 , 17 ] or glucocorticoids .
the gm - csf receptor is expressed on myeloid cells and on some nonhaemopoietic cells such as endothelial cells but not on t cells [ 19 , 20 ] .
the gm - csf receptor is a heterodimer of an -subunit which binds gm - csf with low affinity and a signaling c - subunit which is shared with the il-3 and il-5 receptors .
the c - subunit constitutively associates with janus kinase 2 ( jak2 ) and is tyrosine phosphorylated by it resulting in an assembly of dodecameric signaling complex and initiation of signaling .
the effects of gm - csf are mediated in a dose - dependent manner , by two -chain residues : ser585 and tyr577 . at low concentrations of gm - csf , as in normal healthy tissues ,
signaling occurs via ser585 of the -chain , which leads to activation of the pi-3 kinase pathway and results in myeloid cell survival . at high concentrations of gm - csf , as at the site of inflammation , signaling via ser585
is extinguished and signaling occurs exclusively via tyr577 residue , which activates the jak2/stat5 pathway , ras / mitogen - activated protein kinase pathway and pi-3 kinase pathway , resulting in cell survival , proliferation , and activation [ 2326 ] .
gm - csf stimulates proliferation and activation of macrophages , monocytes , neutrophils , eosinophils , dendritic cells , and microglia [ 1 , 27 ] .
however , since gm - csf - deficient mice did not have a defect in myeloid cell development , a redundant role of gm - csf in myeloid cell development and differentiation under steady state or homeostatic conditions is predicted .
in addition to its function as a hematopoietic growth factor , gm - csf is now recognized to have a variety of functions on mature hemopoietic cells .
gm - csf enhances proinflammatory cytokine production , antigen presentation [ 30 , 31 ] , and phagocytosis [ 3235 ] and promotes leukocyte chemotaxis and adhesion [ 5 , 3638 ] .
gm - csf deficient mice have increased susceptibility to pulmonary [ 28 , 3941 ] and intestinal infections   followed by systemic infection , indicating its importance in maintaining immune homeostasis particularly in the lung and intestines , which are constitutively exposed to pathogens .
gm - csf stimulates the terminal differentiation of macrophages and the acquisition of normal immune functions via the transcription factor pu.1 .
gm - csf also regulates phagocytosis of microbial pathogens by macrophages through the upregulation of pathogen associated molecular pattern ( pamp ) receptors such as c - type lectins including mannose receptors or dectin-1 , scavenger receptors , integrins , or fc receptors via pu.1 [ 24 , 3234 , 43 ] .
complement - dependent phagocytosis is also enhanced by gm - csf to control microbial pathogens .
gm - csf also upregulates the expression of tlr2 , tlr4 , or cd14 and boosts the production of proinflammatory cytokines such as tnf , il-6 , il-12p70 , il-23 , or il-1 [ 24 , 32 , 45 , 46 ] , leading to polarization of macrophages to the m1- ( classic- ) like phenotype , thus , promoting th1th17 responses [ 29 , 47 , 48 ] and contributing to tissue destruction .
on the other hand , m - csf polarizes macrophages to the m2- ( alternative- ) like phenotype , which produces anti - inflammatory cytokines such as il-10 and cc - chemokine ligand 2 ( ccl2 ) and promotes tissue repair and remodeling .
gm - csf also regulates many functions in macrophages including cell adhesion , pulmonary surfactant lipid and protein catabolism , and several important antimicrobial activities such as the production of reactive oxygen species ( ros ) or expression of antimicrobial enzymes .
gm - csf positively regulates the development of migratory cd103cd11b dcs   but negatively regulates the development of resident cd8 dcs .
gm - csf also strongly induces the development of inflammatory monocyte - derived dcs ( modcs ) in vitro .
however , it has not been well established whether gm - csf also regulates the development of modcs in vivo .
it was reported that the number of modcs was increased in gm - csf transgenic mice .
furthermore , nf-b1-dependent gm - csf production in cd4 t cells was reported to be required for the generation of modcs in inflammatory arthritis and antigen - induced peritonitis mouse models .
the number of modcs was markedly reduced in draining lymph nodes from gm - csf/ mice with inflammatory arthritis or in the spleen of mice reconstituted with nf-b1/ cd4 t cells in acute peritonitis , demonstrating that gm - csf contributes to the differentiation of these cells during inflammation in vivo . on the other hand ,
gm - csf was shown to be dispensable for the differentiation of modcs , at least during acute infections , since the number of modcs was not decreased in gm - csf/ mice or gm - csf receptor deficient mice during acute infections [ 55 , 56 ] .
these data indicate that although gm - csf strongly regulates the production of modcs in vitro and in vivo , there may be another gm - csf - independent pathway for the development of modcs .
besides the regulation of dc development , gm - csf also upregulates cross - presentation , bacterial uptake , or production of proinflammatory cytokines such as il-6 or il-23 in resident dcs . in mature neutrophils ,
gm - csf upregulates the expression of the integrin cd11b , which increases cellular adhesion and tissue entry .
gm - csf also upregulates the antimicrobial functions of neutrophils , such as phagocytosis or ros production . however , the expression of pu.1 in neutrophils of autoimmune pulmonary alveolar proteinosis patients was normal , indicating that gm - csf is not involved in neutrophil differentiation . among b cells ,
the innate - like b1 b cells reside predominantly in serosal cavities such as the pleural or peritoneal cavity . in response to microbial infection , b1a b cells ( a subset of b1 b cells ) recognize bacteria via direct tlr - dependent pathogen recognition and differentiate into innate response activator ( ira ) b cells , which produce gm - csf and also express the gm - csf receptor [ 59 , 60 ] .
gm - csf acts on its receptor in an autocrine manner and induces igm production from b cells [ 59 , 61 ] .
mixed chimeric mice with b cell - restricted gm - csf deficiency showed high bacterial titer and morbidity after infection but did not show alveolar proteinosis , indicating that b cell - derived gm - csf is necessary for protective igm responses but dispensable for surfactant clearance by alveolar macrophages .
these data indicate that the cellular source and location of gm - csf is important .
although gm - csf is widely expressed in both stromal and hematopoietic cells , recent murine studies suggest that gm - csf from cd4 t cells is essential in inflammatory mouse models such as experimental autoimmune encephalomyelitis ( eae ) , arthritis models such as collagen - induced arthritis ( cia ) or skg - arthritis , interstitial lung disease in skg mice ( skg - ild ) , peritonitis , or myocarditis [ 3 , 4 , 54 , 57 , 6264 ] .
although gm - csf is known as one of the th17 cytokines , th1 cells and th2 cells also express gm - csf [ 6467 ] .
moreover , recent studies represent the existence of gm - csf - producing th cells distinct from th1 , th2 , or th17 cells [ 62 , 64 ] ( figure 1 ) .
th17 cells have been shown to be strong inducers of tissue inflammation and autoimmune diseases . however , a number of studies determined that il-17 inhibition does not prevent but rather only ameliorates the development of eae [ 3 , 4 , 68 , 69 ] , cia , skg - arthritis , or skg - ild   and that neutralizing il-17 is a rather unsatisfactory method for blocking th17 mediated diseases [ 71 , 72 ] . recently , it was reported that 
classical  th17 cells , which mainly produce il-17 , are not pathogenic and that th17 cells have high plasticity .
th1/17 cells are characterized by their ability to coproduce il-17 , ifn- , and gm - csf and are identified by the coexpression of t - bet , rort , and the chemokine receptors cxcr3 and ccr6 [ 9 , 7478 ] .
human th1/17 cells also express cd161 , a hallmark of th17 progeny cells in humans that is induced by rort [ 76 , 79 , 80 ] .
recent studies report that gm - csf is critical for the pathogenicity of th17 cells [ 3 , 4 ] and the presence of th1/17 cells was observed at the inflammatory site of inflammatory bowel disease ( ibd ) , multiple sclerosis ( ms ) , and juvenile idiopathic arthritis ( jia ) [ 76 , 78 , 81 , 82 ] . in mice ,
il-23 and il-1 induce the production of gm - csf in t cells whereas il-12 suppresses its expression [ 3 , 4 , 77 , 83 ] .
in contrast , in humans il-1 renders th17 cells sensitive to il-12 and both il-1 and il-12 promote the differentiation of th1/17 cells [ 9 , 75 , 81 , 84 , 85 ] ( figure 1 ) .
as described in section 2.3 , gm - csf induces the differentiation of m1-like macrophages and upregulates the production of proinflammatory cytokines such as il-6 , il-12 , il-23 , or il-1 from antigen presenting cells ( apcs ) .
this results in further differentiation of th17 and th1/17 cells , thus creating a positive feedback loop [ 3 , 63 ] .
studies show that gm - csf expression in cd4 t cells is not regulated by t - bet [ 3 , 4 ] and ror - responsive elements are identified in the promoter of the gene encoding gm - csf .
moreover , ectopic rort expression in cd4 t cells results in gm - csf production , indicating that gm - csf production in th1/17 cells is induced by rort .
conversely , rort - deficient cd4 t cells can produce gm - csf , indicating the existence of additional pathways to induce gm - csf production in cd4 t cells .
recently , it was reported that il-2- or il-7-activated stat5 promotes the generation of gm - csf - producing cd4 t cells with low or undetectable expression of t - bet , gata-3 , rort transcripts .
these cells represent a new distinct subset of th cells , namely , th - gm [ 62 , 64 ] . in humans , these th - gm cells are identified as ccr10ccr4cxcr3ccr6 th cells .
it was reported that il-7-activated stat5 directly bound to promoter regions of the gene encoding gm - csf .
the contribution of il-7 has been implicated in autoimmune diseases such as multiple sclerosis or rheumatoid arthritis [ 86 , 87 ] , which also suggests the contribution of th - gm cells in these diseases .
high expression of il-3 , which is also involved in several autoimmune diseases [ 8890 ] , was also reported in th - gm cells .
these cells were reported to be able to induce a more severe experimental autoimmune encephalomyelitis ( eae ) than th17 or th1 cells [ 62 , 64 ] .
it is possible that th - gm cells provide gm - csf to induce the expression of il-23 from apcs and cooperate with th1/17 or th1 cells to exacerbate the development of inflammation .
it was reported that th1 cells also need gm - csf to mediate inflammation in the central nervous system ( cns ) .
however , the amount of gm - csf produced by th1 cells is found to be consistently lower than that produced by th17 cells , particularly during in vitro culture .
although a positive correlation was found between gata-3 cells and gm - csf cells in the nasal mucosa of patients with allergic rhinitis , there is no study to our knowledge that directly analyzes the role of gata-3 in gm - csf production .
further investigation is therefore needed to elucidate the precise mechanism of gm - csf production from cd4 t cells and their contribution to the development of autoimmune and inflammatory diseases .
multiple sclerosis ( ms ) is a chronic inflammatory disease of the central nervous system and is pathologically characterized by demyelination and subsequent axonal degeneration .
past studies have shown that cd4 t cells play a critical role in the development of ms and experimental autoimmune encephalomyelitis ( eae ) , a widely used mouse model of ms .
it has been widely believed that th17 cells are the main encephalitogenic population in autoimmune inflammation ; however , il-17 has been found to be dispensable for the development of eae [ 4 , 93 ] . on the other hand ,
gm - csf deficiency or neutralization of gm - csf has been reported to prevent the onset of eae [ 94 , 95 ] .
the administration of recombinant gm - csf worsened the disease in eae   and elevated concentrations of gm - csf have been reported in the cerebrospinal fluid but not in the serum of patients with relapsing - remitting or secondary progressive ms [ 96 , 97 ] .
recent findings show that gm - csf is secreted by cns - infiltrating helper t cells and is essential for encephalitogenicity in eae [ 3 , 4 , 64 ] .
gm - csf induces the proliferation and activation of microglial cells , which is required for the onset of eae [ 95 , 98 ] .
activated microglial cells produce highly neurotoxic substances such as ros , nitrogen species , glutamate , and tnf- [ 99102 ] .
furthermore , gm - csf - producing cd4 t cells induce the differentiation of neurotoxic m1-like phenotype of microglia   and upregulate the production of proinflammatory mediators such as il-1 , il-6 , and tnf , which contribute to myelin sheath damage , via upregulation of tlr and cd14 expression .
studies also show that gm - csf is required for recruitment of peripheral myeloid cells that contribute to blood - brain barrier ( bbb ) and blood - spinal cord barrier ( bscb ) disruption and demyelization into the cns [ 104 , 105 ] . as we described in section 3.1
, gm - csf induces the polarization of the m1-like macrophage phenotype and exacerbates the positive feedback loop of th17 and th1/17 differentiation .
indeed , an increased m1/m2 profile ratio of monocyte / macrophages in the blood as well as in the cns favors relapsing eae and a reduced m1/m2 ratio promotes an attenuated manifestation of the disease .
the ability of cns - invading myeloid cells to respond to cd4 t cell - derived gm - csf was shown to be vital for the development of eae . taken together , cns - infiltrating cd4 t cells initially activate microglia and induce production of proinflammatory cytokines , which contribute to myelin sheath damage .
this initial neuroinflammation results in bbb destruction and leukocyte infiltration into the cns parenchyma , followed by restimulation of t cells by resident and infiltrating apcs , leading to further apc activation .
these reports indicate that gm - csf plays a central role in ms and indicate that the inhibition of gm - csf will be a useful therapeutic strategy for ms .
mor103 , a fully human monoclonal antibody that binds human gm - csf , is currently being tested in a phase ib trial for ms   ( table 1 ) .
rheumatoid arthritis ( ra ) is a systemic chronic autoimmune disease characterized by persistent and erosive inflammatory polyarthritis .
recent studies indicate that gm - csf plays a central role in the pathogenesis of ra as in ms , by activating or promoting differentiation and survival of macrophages and neutrophils [ 109 , 110 ] .
the concentrations of gm - csf were elevated in the synovial fluid and plasma of ra patients [ 111 , 112 ] .
a case report showed that the administration of recombinant gm - csf exacerbated the disease activity of ra .
the frequency of gm - csf - producing th cells was significantly increased in synovial fluid cells compared to peripheral blood mononuclear cells ( pbmcs ) in patients with juvenile idiopathic arthritis ( jia ) and correlated with erythrocyte sedimentation rate ( esr ) levels [ 81 , 114 ] .
synovial gm - csf - producing t cells were predominantly cd161 positive and coexpressed ifn- but not il-17 , indicating that these cells are th1/17 cells .
alternatively , human synovial fibroblasts and chondrocytes were also reported to produce gm - csf in response to il-1 and tnf stimulation [ 115 , 116 ] .
the contribution of gm - csf in the development of arthritis was also reported in several mouse models of arthritis . in the collagen - induced arthritis ( cia ) model ,
gm - csf deficient mice failed to develop arthritis , and the administration of anti - gm - csf neutralizing antibodies ameliorated existing disease , prevented disease progression , and reduced the concentrations of tnf and il-1 in the joints of treated mice . on the other hand , gm - csf administration exacerbated arthritis in cia . in skg mice , another model of autoimmune arthritis , gm - csf ,
upregulated proinflammatory cytokine production such as il-1 or il-6 from macrophages in a dose dependent manner [ 63 , 120 ] .
this in turn induced further differentiation and expansion of il-17-producing and gm - csf - producing cd4 t cells .
the progression of arthritis in skg mice was inhibited by the neutralization of gm - csf and slightly by the neutralization of il-17a , indicating that gm - csf plays a more critical role than il-17a in skg arthritis .
mavrilimumab , a fully human anti - gm - csf receptor  antibody , is currently being developed and a phase ii study in ra patients reported significant efficacy with no serious adverse events such as pulmonary alveolar proteinosis .
in this study of patients with active ra despite methotrexate treatment , 55.7% of all participants treated with mavrilimumab met the primary end point of achieving 1.2 decrease from baseline in the disease activity score ( das28-crp ) at week 12 . at the highest dose of mavrilimumab ( 100  mg ) ,
66.7% of subjects met the primary end point versus only 34.7% of the subjects in the placebo group .
mor103 , which is also being tested for ms , has shown preliminary evidence of efficacy in a phase ib / iia trial for patients with active ra .
subjects receiving higher doses of mor103 ( 1.0 and 1.5  mg / kg ) showed significant improvement in das28 scores and joint counts and significantly higher european league against rheumatism response rates than subjects receiving placebo .
both mavrilimumab and mor103 showed rapid treatment responses and provided evidence of clinical efficacy that support further clinical investigation .  
a list of ongoing / completed clinical trials targeting gm - csf or its receptor is presented in table 1 , with more information available at clinicaltrials.gov .
pulmonary alveolar proteinosis ( pap ) is a rare syndrome characterized by the accumulation of surfactant in pulmonary alveoli resulting in varying degrees of respiratory insufficiency and myeloid cell dysfunction leading to increased risk of infection [ 123 , 124 ] .
several clinical forms of pap have been identified including autoimmune pap caused by gm - csf autoantibodies , hereditary pap caused by gm - csf receptor mutations , and secondary pap associated with various underlying clinical disorders which is presumed to cause this syndrome by reducing alveolar macrophage numbers or function .
it is also reported that gm - csf deficient mice develop abnormal lung histology that is virtually indistinguishable from human pap .
pulmonary surfactant is tightly regulated by balanced production , secretion , reuptake , and catabolism within alveoli .
gm - csf regulates surfactant catabolism in alveolar macrophages via pu.1 but does not regulate surfactant endocytosis or uptake and catabolism of surfactant by alveolar epithelial cells type ii ( aec - ii ) [ 32 , 127 ] .
gm - csf is also required to stimulate numerous immune functions and terminal differentiation of alveolar macrophages   and induction of igm production from b cells [ 60 , 61 ] .
therefore , gm - csf deficient mice have high susceptibility to pulmonary infections [ 28 , 3941 ] accompanied by systemic infections . based on the pathogenesis of pap , several new therapeutic approaches for treating autoimmune pap targeting gm - csf are in clinical trials , including plasmapheresis , gm - csf administration [ 129 , 130 ] , and rituximab [ 131 , 132 ] .
the mechanism of pulmonary fibrosis in interstitial lung disease ( ild ) has been studied using idiopathic pulmonary fibrosis ( ipf ) or a bleomycin - induced mouse model of pulmonary fibrosis . pulmonary fibrosis in ipf
is considered to be inflammation - independent and mainly initiated by tgf- produced by damaged epithelial cells .
in fact , anti - inflammatory therapies have little benefit in ipf [ 133135 ] .
however , neutrophils , which produce ros , mmps , neutrophil elastase , or myeloperoxidase and cause lung parenchymal and stromal cell injury [ 136138 ] or th2 cytokines such as il-4 or il-13 , which induce fibroblast differentiation or extracellular matrix synthesis [ 139 , 140 ] , have been reported to contribute to lung fibrosis to some extent .
additionally , gm - csf was reported to take part in the progress of pulmonary fibrosis .
it was reported that tnf-induced endothelin-1 ( et-1 ) upregulates gm - csf production from airway smooth muscle cells ( asmcs )   and that gm - csf was increased in the bronchoalveolar lavage fluid ( balf ) of patients with pulmonary fibrosis [ 142 , 143 ] .
gm - csf stimulates macrophages to release profibrotic cytokines and also induces fibrosis by direct stimulation of airway smooth muscle cells [ 144 , 145 ] .
in fact , overexpression of gm - csf in the lungs led to severe neutrophil , eosinophil , and macrophage infiltration and fibrotic reactions [ 145147 ] .
in contrast with idiopathic pulmonary fibrosis ( ipf ) , connective tissue disease - associated ild ( ctd - ild ) is often characterized by a clearer response to immunosuppression , indicating that autoimmune / inflammatory mechanisms play a more significant and central role in the pathogenesis of ctd - ild [ 148 , 149 ] .
skg mice , a model of autoimmune arthritis , were reported to develop chronic - progressive interstitial lung disease ( ild ) that histologically resembles ctd - ild [ 63 , 150 , 151 ] . recently
, it was reported that ild in this mouse was characterized by massive infiltration of th17 cells , gm - csf - producing cd4 t cells , and cd11bgr1 neutrophils with fibrosis .
naive skg t cells were skewed to differentiate into gm - csf - producing cells .
furthermore , gm - csf secreted by t cells enhanced il-6 and il-1 production by macrophages , which in turn enhanced differentiation of il-17a and/or gm - csf - producing t cells and infiltration of neutrophils into the lungs .
neutralization of gm - csf completely blocked the development of this ild , whereas neutralization of il-17a did not , showing that gm - csf not il-17a is critical for the development of ild in skg mice .
importantly , neutralization of gm - csf ameliorated ild in skg mice even after the onset of ild , suggesting that gm - csf inhibition is a useful therapeutic strategy for ctd - ild .
mavrilimumab , a fully human anti - gm - csf receptor  antibody and mor103 , a fully human monoclonal anti - gm - csf antibody , are undergoing clinical trials in ra patients [ 121 , 122 ] .
recent developments suggest that the development of crohn 's disease ( cd ) is caused by a mucosal innate immunodeficiency with a variety of genetic defects   and a dysfunction of granulocytes , macrophages , and intestinal epithelial cells [ 153 , 154 ] . in the intestine
, gm - csf contributes to gut barrier function and resistance to bacterial translocation by promoting the recruitment and activation of monocytes / macrophages , neutrophils , and dcs .
gm - csf also promotes tissue repair via increased intestinal epithelial cell proliferation and increased macrophages as effectors of wound healing [ 155157 ] .
however , in cd patients , the inherent defects in the mucosal barrier increase the translocation of pathogens to the bowel tissue .
moreover , increased levels of gm - csf autoantibodies have been reported in patients with ileal / ileocolonic cd , compared with those with colon involvement only , ulcerative colitis ( uc ) patients , or healthy controls .
the high levels of gm - csf antibodies directly correlated with disease activity and inversely correlated with neutrophil phagocytic activity . increased gm - csf autoantibodies affect mucosal integrity , bacterial killing and neutrophil migration , proliferation , and survival .
gm - csf deficient mice also developed a more severe intestinal and systemic infection after enteric infection   and were more susceptible to acute dextran sodium sulfate- ( dss- ) induced colitis .
both severity of infection and colitis were largely prevented by gm - csf administration [ 160 , 161 ] .
on the other hand , gm - csf overexpression in the stomach leads to autoimmune gastritis   and experimental peritonitis or intraperitoneal lps exposure in gm - csf deficient mice resulted in blunted proinflammatory responses and mortality .
the expression of gm - csf at the mrna level increases from the stomach distally down through the colon , indicating that gastrointestinal expression of gm - csf expression parallels bacterial localization .
these data indicate that the threshold of gm - csf levels between inflammation and immune homeostasis can vary with tissue location or organs .
these findings indicate that administration of gm - csf could be beneficial for the treatment for cd patients .
initial reports indicated that the administration of gm - csf in cd patients with moderate to severe disease activity had a high rate of clinical response and remission with minimal adverse effects [ 165 , 166 ] .
moreover , a randomized phase ii clinical trial demonstrated that gm - csf was significantly more effective than placebo in obtaining a corticosteroid - free clinical remission .
conversely , a recent large randomized trial found that it was no more effective than placebo for induction of clinical remission or improvement in active cd .
cd patients are known to have substantial heterogeneity in pathogenic mechanisms and so gm - csf as a therapy may only be appropriate for a subgroup of patients . additionally , it is also important to verify the efficacy of gm - csf not only for the induction of remission but also for the maintenance of remission
. therefore , further studies are needed to elucidate the efficacy of gm - csf as a treatment as well as the appropriate patient character or phase of disease to apply gm - csf administration as a therapy .
gm - csf also was reported to take part in th2 response in allergic airway inflammation via activation of dcs [ 169171 ] . in mouse models of asthma ,
allergen - exposed epithelial cells release gm - csf which activates dcs and also prolongs eosinophil survival [ 170 , 172 ] .
consequently , gm - csf neutralization reduced allergic hyperresponsiveness in mice models [ 169 , 170 , 172 ] .
anti - gm - csf antibody , is tested in a phase ii trial for severe asthma ( table 1 ) .
gm - csf plays pivotal roles not only in maintaining immune homeostasis but also in exacerbating inflammatory reactions .
recent findings indicate that gm - csf inhibition will be an attractive therapeutic strategy for many autoimmune and inflammatory diseases .
studies also indicate that it is necessary to monitor possible side effects such as pap or cd , although gm - csf inhibition has no demonstrated serious adverse reactions so far , which is indicative of its wide therapeutic index [ 63 , 173 , 174 ] .
further studies are necessary to identify the molecular mechanisms that regulate gm - csf production and the role of gm - csf in the development of inflammatory diseases to devise preventive or curative strategies for autoimmune and inflammatory diseases .
 granulocyte macrophage - colony stimulating factor ( gm - csf ) is a hematopoietic growth factor , which stimulates the proliferation of granulocytes and macrophages from bone marrow precursor cells . in autoimmune and inflammatory diseases , 
 th17 cells have been considered as strong inducers of tissue inflammation . 
 however , recent evidence indicates that gm - csf has prominent proinflammatory functions and that this growth factor ( not il-17 ) is critical for the pathogenicity of cd4 + t cells . 
 therefore , the mechanism of gm - csf - producing cd4 + t cell differentiation and the role of gm - csf in the development of autoimmune and inflammatory diseases are gaining increasing attention . 
 this review summarizes the latest knowledge of gm - csf and its relationship with autoimmune and inflammatory diseases . 
 the potential therapies targeting gm - csf as well as their possible side effects have also been addressed in this review . 
1. Introduction
2. Biology of GM-CSF
3. T Cell and GM-CSF
4. GM-CSF in Autoimmune and Inflammatory Diseases
5. Conclusion