interleukin-6 ( il-6 ) , initially designated as a b cell differentiation factor 1 , is a representative cytokine featuring redundancy and pleiotropic activity 2 - 4 . in the early phase of infectious inflammation
, il-6 is produced by monocytes and macrophages immediately after the stimulation of toll - like receptors ( tlrs ) with distinct pathogen - associated molecular patterns ( pamps ) 5 . in noninfectious inflammations , such as burn or traumatic injury , damage - associated molecular patterns ( damps ) from damaged or dying cells stimulate tlrs to produce il-6 6 .
this acute il-6 expression plays a central role in host defense by stimulating various cell populations .
when acting on hapatocytes , il-6 strongly induces a broad spectrum of acute - phase proteins such as c - reactive protein ( crp ) , serum amyloid a ( saa ) , fibrinogen , hepcidin , haptoglobin , and antichymotrypsin , whereas it reduces albumin , cytochrome p 450 , fibronectin , and transferrin 7 , 8 
 ( figure 1 ) .
crp is a good biomarker of inflammation and is used as such in clinical laboratory tests .
if the free concentration of the anti - interleukin 6 receptor antibody , tocilizumab is maintained in serum at more than 1 g / ml , crp remains negative 10 , so that the serum crp level is a hallmark for checking whether il-6 activity is completely blocked in vivo .
continuously high levels of hepcidin induced by il-6 block iron transporter ferroportin 1 in macrophages , hepatocytes , and gut epithelial cells and lead to hypoferremia and anemia of chronic inflammation 11 , whereas long - term high levels of saa result in amyloid a amyloidosis 12 . in lymphocytes
when cd4-positive nave t cells are primed , a specific cytokine prompts their differentiation into an effector t cell subset . il-6 together with tgf- preferentially promotes differentiation of il-17-producing t helper cells ( th17 ) that play a crucial role in the induction of autoimmune tissue injury , whereas il-6 inhibits tgf--induced regulatory t cell ( treg ) differentiation 13 , 14 .
the resultant th17/treg imbalance leads to breakage of immunological tolerance and is of pathological importance for the development of various autoimmune and chronic inflammatory diseases 15 .
the function of il-6 in hematopoiesis is to induce maturation of megakaryocytes into platelets as well as activation of hematopoietic stem cells 17 .
il-6 production in bone marrow stromal cells generates the receptor activator of nf - kappab ligand ( rankl ) , which is an essential factor for the differentiation and activation of osteoclasts and bone resorption , thus leading to osteoporosis 18 .
enhanced angiogenesis and increased vascular permeability are pathological features of inflammation , and these characteristics are due to the excess production of vascular endothelial growth factor ( vegf ) , which is induced by il-6 in inflamed lesions such as seen in synovium tissue of rheumatoid arthritis 19 .
the promotional activities of il-6 , such as the proliferation of keratinocytes or collagen production in dermal fibroblasts , may contribute to autoimmune skin diseases including psoriasis and systemic sclerosis 20 , 21 .
furthermore , il-6 stimulates the growth of cells such as myeloma / plasmacytoma cells and mesangial cells 22 - 24 .
il-6 triggers signal transduction after binding to the il-6 receptor ( il-6r ) 25 , 26 .
there are two forms of il-6r , a transmembrane 80-kda form with a short cytoplasmic domain and a soluble form ( sil-6r ) . after binding of il-6 to transmembrane il-6r , the resultant il-6/il-6r complex associates with gp130 27 - 29 , and the activated il-6 receptor complex is formed as a hexameric structure consisting of two molecules each of il-6 , il-6r and gp130 ( so - called a classical signaling ) 30 , 31 .
the expression of transmembrane il-6r is limited to a few cell types but the il-6/sil-6r complex can also transduce the il-6 signal to various cells which do not express transmembrane il-6r but express gp130 ( known as a trans - signaling mechanism ) 32 , so that il-6 affects a wide variety of cells .
when il-6 is synthesized transiently , it promptly participates in the host defense against environmental stress such as infection and injury and at the same time provides an sos ( warning ) signal by triggering a broad spectrum of biological events .
once the source of stress is removed from the host , il-6-mediated activation of the signal transduction cascade is terminated by negatively regulatory systems in conjunction with the normalization of serum il-6 and crp levels . however , dysregulated persistent il-6 production has been implicated in the development of various autoimmune , chronic inflammatory diseases and even cancers 2 - 4 , 33 .
the reason(s ) why such dysregulated continuous il-6 production is induced remains to be clarified and elucidation of the mechanism(s ) underlying persistent il-6 synthesis in diseases is of particular importance to make their pathogenesis clear .
it was found that in human immunodeficiency virus ( hiv)-positive cases of multicentric castleman 's diseases all patients were infected with the kaposi sarcoma - associated herpes virus ( kshv ) and that sustained synthesis of both virus - derived il-6 , which directly binds to and stimulates human gp130 , and of host - derived human il-6 contribute to the development of the disease 34 .
moreover , numerous animal models of diseases have also disclosed the pathologic role of il-6 in disease development and that il-6 blockade by means of gene - knockout or administration of anti - il-6 or anti - il-6r antibody can suppress such disease development either preventively or therapeutically .
for example , il-6 blockade strategy demonstrably limited susceptibility to castleman 's disease - like symptoms in il-6 transgenic mice 35 , as well as in various mouse models of rheumatoid arthritis 36 - 48 , systemic lupus erythematosus 49 - 51 , scleroderma 52 , 53 , c - peptide - induced myositis 54 , experimental autoimmune uveoretinitis 55 , 56 , experimental autoimmune encephalomyelitis 57 , and many other diseases .
because of the pathological role of il-6 in various diseases , blockade of il-6 was expected to constitute a novel treatment strategy for these diseases 3 , 58 , 59 .
consequently , a humanized anti - human il-6r monoclonal antibody ( chemical name : tocilizumab , generic name : actemra outside of the eu or roactemra inside the eu ) was developed , by grafting the complementarity - determining regions of a mouse anti - human il-6r antibody onto human igg1 .
the resultant tocilizumab then blocks il-6-mediated signal transduction by inhibiting il-6 binding to transmembrane and soluble il-6 receptors .
clinical trials of tocilizumab have demonstrated its outstanding efficacy for rheumatoid arthritis 60 - 66 , systemic juvenile idiopathic arthritis 67 - 71 and castleman 's disease 72 , 73 . for patients with moderately to severely active rheumatoid arthritis , tocilizumab
is now being used as an innovative drug in more than 90 countries worldwide . as a monotherapy or in combination with disease - modifying antirheumatic drugs
, it has significantly suppressed the disease activity and radiographically detected progression of joint deformity , thus improving daily functional activity .
tocilizumab was also approved as the first line biologic for the treatment of systemic juvenile idiopathic arthritis in japan , india , usa and eu and for castleman 's disease in japan and india .
furthermore , favorable results of recent pilot studies , case series or case studies have suggested that tocilizumab may have broad application for other diseases .
these diseases include systemic autoimmune diseases such as systemic lupus erythematosus 74 - 76 , systemic sclerosis 77 , polymyositis 78 , vasculitis syndrome including giant cell arteritis 79 - 84 , takayasu arteritis 79 , 82 , 85 - 87 , cryoglobulinemia 88 , myeloperoxidase - antineutrophil cytoplasmic antibody - associated crescentic glomerulonephritis 89 and rheumatoid vasculitis 90 .
the application of tocilizumab may also extend to organ - specific autoimmune diseases including crohn 's disease 91 , relapsing polychondritis 92 , 93 , acquired hemophilia a 94 , autoimmune hemolytic anemia 95 , 96 , as well as to chronic inflammatory diseases such as adult - onset still 's disease 97 - 113 , amyloid a amyloidosis 114 - 120 , polymyalgia rheumatica 79 , 84 , 121 , remitting seronegative symmetrical synovitis with pitting edema 122 , behcet 's disease 123 , 124 , uveitis 125 , graft - versus - host diseases 126 , 127 , and tumor necrosis factor receptor - associated periodic syndrome 128 ( table 1 ) .
some studies have reported that tocilizumab is efficacious for spondyloarthritis 129 - 135 , although others observed only minor effects 136 - 138 .
in addition , tocilizumab is reportedly effective for pulmonary arterial hypertension 139 - 141 , atopic dermatitis 142 , and sciatica 143 .
finally , it was observed that during tocilizumab treatment of patients with rheumatoid arthritis , hba1c levels and insulin resistance indices such as the homeostasis model assessment of insulin resistance ( homa - ir ) and the leptin - to - adiponectin ratio improved 144 , 145 , while serum levels of reactive oxygen metabolites decreased 146 .
it can thus be expected that long - term tocilizumab treatment may offer protection against the progression of atherosclerosis leading to cardiovascular events 147 .
indeed , large - scale genetic analyses demonstrated a causal association between il-6r - related pathways and coronary heart disease 148 , 149 , and a randomized , open - label , parallel - group , multicenter study to evaluate the rate of cardiovascular events of tocilizumab in comparison to a tnf inhibitor , etanercept in patients with rheumatoid arthritis ( clinicaltrials.gov , identifier : nct01331837 ) is now in progress . to establish broad clinical indications for tocilizumab for various diseases ,
the current clinical trials are listed in table 2 . on the basis of the pathologic role of il-6 and the outstanding beneficial effect of tocilizumab ,
targeting il-6 is a rational strategy for the treatment of various diseases and other biologics of il-6 inhibitors are also being developed 32 .
these include fully human anti - il-6r , anti - il-6r nanobody , anti - il-6 antibody , and anti - il-6/anti - igg avimer protein consisting of the igg - binding domain fused to the n - terminus of a 3-domain il-6 binding region , which results in a 19-kda heterotetrameric avimer .
these novel biologics block il-6-mediated both classical and trans - signaling pathway by inhibiting il-6 binding to both transmembrane and soluble il-6r .
by contrast , the fusion protein soluble gp130-fc selectively targets il-6/sil-6r trans - signaling pathway .
it is hypothesized that il-6 trans - signaling is a local and temporal danger signal with fewer and less important physiological functions under non - stressed conditions than classical signaling on the basis of several animal models 32 , 150 .
il-6 participates in the host defense against environmental pathogens , whereas dysregulation of il-6 production has been implicated in the development of various autoimmune and chronic inflammatory diseases 2 - 4 , 33 .
the pleiotropic activity of il-6 also indicates that il-6 blockade represents a rational treatment strategy for various diseases .
a good example of the efficacy of such treatment is the dramatic improvement engendered by tocilizumab in amyloid a amyloidosis and anemia of inflammation through inhibition of their respective responsible proteins , saa and hepcidin synthesis 151 , 152 .
however , the mechanisms through which tocilizumab exerts its therapeutic effects on various phenotypically different autoimmune and inflammatory diseases are not yet well understood . in recent years , it has been shown that th17 and/or th1 > >
il-6 , in combination with tgf- , promotes the differentiation of nave t cells into th17 , but inhibits tgf--induced treg differentiation , indicating that il-6 is a very important factor for determining the th17/treg balance 14 .
dysregulated il-6 production leads to predominance of th17 over treg but anti - il-6r antibody can repair this imbalance .
it has been demonstrated in several animal disease models that il-6 blocking suppresses antigen - specific th17 and/or th1 differentiation but induces antigen - specific treg 47 , 48 , 55 - 57 .
furthermore , it has been shown that tocilizumab in fact corrects th17/treg imbalance in rheumatoid arthritis patients 153 . in another study
, it was found that tocilizumab induced a significant reduction in the peripheral pre - switch and post - switch memory b cells of rheumatoid arthritis patients 154 and that tocilizumab but not the tnf inhibitor significantly reduced somatic hypermutation in immunoglobulin gene rearrangements in pre - switch memory b cells 155 , thus suggesting that modulation of memory b cells may be one possible target for tocilizumab .
moreover , tocilizumab treatment led to a reduction in the pathologic cd38cd19igd plasma cells of sle patients 74 and could lessen the survival of plasmablasts , which produce the anti - aquaporin 4 antibody in neuromyelitis optica 156 .
these findings suggest that the clinical effect of tocilizumab is also mediated through its inhibition of pathological autoantibody production .
because of the therapeutic efficacy of tocilizumab , il-6 plays a major role in the onset or development of various phenotypically different diseases .
il-6 is produced by a panoply of cells including monocytes , macrophages , dendritic cells , t and b cells , neutrophils , mast cells , fibroblasts , synovial cells , keratinocytes , endothelial cells , stromal cells , mesangial cells , glial cells , neurons , chondrocytes , osteoblasts , smooth muscle cells , and others in response to various stimuli 2 - 4 , 33 .
such phenotypic difference of diseases is conceivably due to differences in cells which generate il-6 through abnormal transcriptional activation of the il-6 gene 157 , 158 and/or inhibition of il-6 mrna degradation 159 , 160 , or dose - dependent effects of il-6 produced by cells recruited into the organs .
some virus products from kshv , human immunodeficiency virus ( hiv ) , human lymphotropic virus-1 ( htlv-1 ) and hepatitis b virus have been reported to affect il-6 gene activation and/or mrna degradation 161 - 168 .
therefore clarification of the cell source of il-6 production and of the mechanism(s ) through which dysregulated continuous il-6 synthesis is induced constitutes an important issue for future studies into the pathogenesis of diseases .
 interleukin ( il)-6 , a cytokine featuring redundancy and pleiotropic activity , contributes to host defense against acute environmental stress , while dysregulated persistent il-6 production has been demonstrated to play a pathological role in various autoimmune and chronic inflammatory diseases . 
 targeting il-6 is thus a rational approach to the treatment of these diseases . indeed , clinical trials of tocilizumab 
 , a humanized anti - il-6 receptor antibody have verified its efficacy and tolerable safety for patients with rheumatoid arthritis , castleman 's disease and systemic juvenile idiopathic arthritis , resulting in approval of this innovative biologic for treatment of these diseases . moreover , a considerable number of case reports and pilot studies of off - label use of tocilizumab point to the beneficial effects of tocilizumab for a variety of other phenotypically different autoimmune and chronic inflammatory diseases . 
 elucidation of the source of il-6 and of mechanisms through which il-6 production is dysregulated can thus be expected to lead to clarification of the pathogenesis of various diseases . 
Introduction
Pathological Role of IL-6 in Development of Diseases
Targeting IL-6: All the Way to Treat Autoimmune and Inflammatory Diseases
Future Directions