toll - like receptor ( tlr ) agonists such as endotoxins initiate the synthesis of the inactive il-1 precursor ( fig .
although most of the il-1 precursor is in the cytosol , a fraction moves into specialized secretory lysosomes ( 1 ) .
the next step is the conversion of the inactive procaspase-1 to active caspase-1 by a complex of proteins termed the
current thinking is that in resting cells procaspase-1 is bound to a large inhibitor molecule , which prevents its activation . during initiation of il-1 synthesis
, there is activation of caspase-1 , which then processes the il-1 precursor into a mature form ready for secretion .
processing and release are closely linked ( fig . 1 , c and d ) .
activation of the nucleotide p2x7 receptor triggers the efflux of potassium ions out of the cell , and within minutes the secretory lysosomes begin releasing their contents of processed il-1 into the extracellular milieu . in support of the role of p2x7 , overexpression of the receptor increases the secretion of il-1 ( 3 ) and
the small peptide ll37 released from activated neutrophils and epithelial cells also stimulates the release of processed il-1 via the p2x7 receptor ( 5 ) .
the efflux of potassium ions signals the influx of calcium ions ( 3 ) , which in turn activate phospholipases ( 6 ) .
it appears that calcium - independent phospholipase a2 is required for caspase-1 processing in the specialized lysosomes , whereas phosphatidylcholine - specific phospholipase c is required for lysosomal exocytosis and release ( 6 ) .
dysregulation in any of these steps might account for increased secretion of il-1 and for il-1mediated diseases .
steps in the processing and secretion of il-1. ( a ) tlr ligands such as endotoxin trigger gene expression and synthesis of the il-1 precursor , which remains diffusely in the cytosol . in the same cell , inactive procaspase-1
is bound to components of the il-1 inflammasome , which contains the products of the nalp-3 gene .
the il-1 inflammasome is kept in an inactive state by binding to a large molecular weight putative inhibitor .
( b ) after tlr signals , there is a transient uncoupling of the inhibitor and nalp-3 gene products from procaspase-1 , which then colocalizes with the il-1 in secretory lysosomes .
( c ) activation of the nucleotide receptor p2x7 by atp or ll37 initiates the efflux of potassium from the cell via a potassium channel .
( d ) the efflux of potassium ions results in the influx of calcium ions , which in turn activate phospholipases .
phosphatidylcholine - specific phospholipase c ( pc - pla-2 ) facilitates lysosomal exocytosis and secretion of il-1 .
sojia ( also known as systemic juvenile rheumatoid arthritis ) is a devastating , systemic inflammatory disease that affects growing children for which there are few treatment options other than high dose corticosteroid treatment . in this issue ,
pascual and colleagues show that blocking il-1 activity with an il-1 receptor antagonist ( il-1ra , anakinra ) resulted in convincing clinical and hematological responses in nine patients with sojia ( 7 ) .
resolution of clinical symptoms including fever , marked leukocytosis , thrombocytosis , elevated erythrocyte sedimentation , anemia , and arthritis were rapid and sustained .
the efficacy of il-1ra in these children contrasts sharply to that of blocking tnf in sojia .
neutralization of tnf , a successful treatment in some patients with rheumatoid arthritis , is now discredited in sojia since the tnf inhibitors etanercept and infliximab are associated with treatment failures , worsening of disease and/or exacerbations of other autoimmune diseases in these patients .
based on the present study and a similar observation ( 8) , blocking il-1 may become the standard of therapy for sojia . at present , only il-1ra is approved for use in humans , but other agents such as anti  il-1 monoclonal antibodies or the il-1 trap molecule ( 9 ) reduce il-1 activity and are likely to be effective .
the rapid resolution of clinical , hematological , and biochemical manifestations of sojia after a few days of il-1ra treatment is reminiscent of the treatment of refractory adult onset still 's disease , a systemic inflammatory disease of adults characterized by similar manifestations of disease seen in sojia .
reduction or complete withdrawal of long - term steroid treatment was achieved without a rebound in disease activity , as is also the case in adult onset still 's disease patients treated with il-1ra . for growing children ,
in addition , il-1ra therapy in rheumatoid arthritis patients does not interfere with tetanus immunization , suggesting that this treatment will not interfere with childhood immunizations .
pascual and coworkers took their investigation of disease mechanisms a step further than most studies .
they added 20% serum from four sojia patients or from healthy controls to peripheral blood mononuclear cells ( pbmcs ) of healthy donors , and changes in gene expression were assessed by microarray analysis ( 7 ) .
why these four sera of the 16 patients available to the authors were selected is not specified , nor is the reason for using 20% serum .
nevertheless , increases in gene expression of cytokines , cytokine receptors , cell adhesion molecules , and other markers of inflammation were observed in pbmcs incubated with patient sera but not control sera .
the authors found that incubating pbmcs with 20% serum from sojia patients increased secretion of il-1 compared with autologous sera .
furthermore , it appeared that the sera from patients with systemic disease induced more il-1 secretion compared with patients with only active arthritis .
it may be concluded that 20% serum from patients with sojia contains enough stimulant(s ) to increase a portfolio of proinflammatory genes as well as induce secretion of il-1 from healthy pbmcs , and that autologous sera does not contain such stimulants . in my opinion , however , such methods do not support the concept that disease is caused by a circulating factor(s ) ; rather , the effects of sera on cultured cells may be an epiphenomenon .
presence of tlr ligands , such as bacterial lipopolysaccharide , in sojia sera would yield the same results , and a combination of particular serum acute phase reactants could also contribute to the observation .
if the authors had added il-1ra to the cultures , they could have at least observed whether the serum stimulant(s ) was il-1 itself .
the authors also examined steady - state gene expression in pbmcs from 16 sojia patients with active disease and compared the results to pbmcs from 12 healthy children .
many of the same genes induced by sojia sera were spontaneously increased in the pbmcs of these 16 patients .
most notable and significant were the genes encoding il-1 , the il-1 decoy receptor , cyclooxygenase-2 , tlr-2 , and the complement receptor c1q .
pentraxin-3 , an il-1inducible gene ( 11 ) , was also highly overexpressed , and being an acute phase protein , it likely contributes to the high sedimentation rate of red blook cells in sojia .
some genes that were up - regulated by the sojia sera were not increased in steady - state mrna from pbmcs of the 16 patients , including several chemokines and fibronectin , casting doubt on the relevance of the high expression level these genes have in serum studies .
another potentially relevant gene overexpressed in sojia pbmcs is a potassium channel gene kcnj15 . as discussed above , influx of potassium ions
is a trigger for activation of caspase-1 and secretion of il-1 in response to activation of the nucleotide receptor p2x7 .
measurement of circulating il-1 is not a reliable indicator of a role for this cytokine in disease , nor does it provide rationale for selection of a therapeutic intervention such as il-1ra .
il-1 is a highly active cytokine in humans ; injecting a few nanograms per kilogram results in fever , neutrophilia , thrombocytosis , acute phase proteins , and circulating il-6 ( for review see reference 12 ) .
thus , circulating levels of il-1 in the picomolar range may easily escape detection by routine elisas or similar methods .
although there are numerous reports that circulating cytokine levels correlate with severity in a variety of diseases , it is only specific blockade or neutralization of a cytokine that provides a convincing case for causation . for this reason ,
it is a general concept that il-1mediated disease severity is regulated at the level of ligand production and activity , and not at the receptor level .
for example , il-1 type i receptors are expressed on all cells in healthy individuals and increases of only two- or threefold occur in disease . on the other hand , in circulating monocytes and bone marrow macrophages from healthy individuals ,
il-1 gene expression is absent but increases at least 100-fold when stimulated with microbial products or inflammatory molecules , including products of activated t cells .
the total amount of il-1 precursor that is synthesized , however , does not necessarily equate to the amount of active il-1 that is produced , as the caspase-1dependent conversion of il-1 precursor to an active secreted cytokine is a tightly controlled event , despite the presence of constitutive procaspase-1 in the same cell .
hence , the increase in il-1 secretion from pbmcs of sojia patients is a highly relevant observation .
the study by pascual and coworkers provides evidence for increased secretion of il-1 by freshly cultured pbmcs from these patients compared with pbmcs from healthy subjects ( 7 ) . in the absence of exogenous stimulation , cultured pbmcs from healthy subjects
do not release il-1 , but upon stimulation synthesize the il-1 precursor and release the processed form of il-1 into the supernatant .
however , more than 50% of the total il-1 precursor synthesized remains inside monocytes from healthy donors .
the amount of il-1 released from pbmcs of five sojia patients was more than 10-fold greater than five healthy controls ( 7 ) .
in the same cultures , the release of tnf and il-6 was similar for healthy and affected subjects , suggesting that the elevated release of il-1 was not due to increased monocyte numbers or increased activation of sojia pbmcs .
unfortunately , il-1 secretion was induced using the unorthodox combination of pma plus ionomycin , whereas most studies of dysfunctional il-1 release use tlr agonists .
nevertheless , the disease - related increase in il-1 secretion may explain the role for il-1 and the responses to il-1ra in these patients who failed to respond to conventional treatments .
increased secretion of il-1 from cultured pbmcs has also been reported for a growing number of inherited , chronic autoinflammatory syndromes , each of which responds to il-1ra ( 1316 ) . in these syndromes , increased secretion of il-1 is due to a single amino acid mutation in the nalp-3 gene , which controls the activation of caspase-1 found in the il-1 inflammasome ( 17 ) .
similar to the situation in sojia , circulating levels of il-1 are not detected in these patients ( 13 ) but increased secretion of il-1 is observed in vitro .
the single point mutation in the nalp-3 gene causes the loss of tight control of il-1 processing . as a result ,
relatively minor stresses such as exposure to cold results in increased secretion of il-1 with consequent systemic disease ( 13 ) .
it appears that the nalp-3 gene provides an important roadblock to control the secretion of il-1 and raises the issue of a defective roadblock in sojia .
although the reason for the increased secretion of il-1 in the sojia patients remains unclear , both sojia patients and patients with nalp-3 mutations share the phenotype of systemic disease and increased secretion of processed il-1 in vitro .
there are chronic inflammatory syndromes without mutations in the nalp-3 gene but nevertheless elevated il-1 release in vitro and also respond to il-1ra therapy ; presently , these are mutation - negative neonatal onset multisystem inflammatory disease ( nomid ; reference 18 ) , pyogenic arthritis , pyoderma gangrenosum , acne syndrome ( papa ; reference 19 ) , and familial mediterranean fever ( fmf ; reference 20 ) .
both papa and fmf are genetic diseases associated with the intracellular protein pyrin , which participates in maintaining procaspase-1 as an inactive enzyme .
mutations of the pyrin gene in mice , similar to those found in humans with fmf , result in increased caspase-1 activity and increased secretion of il-1 ( 21 ) .
although these systemic , multisystem syndromes are not common diseases , they reveal a fundamental role for il-1 in systemic inflammation regardless of the cause . as shown in fig .
these are recurrent fevers , neutrophilia , thrombocytosis , elevated serum amyloid a and c  reactive protein , and anemia .
hearing loss , developmental delay , and aseptic meningitis can also be observed in childhood .
the endothelium is a prime target for il-1mediated inflammation as il-1 receptors on the endothelium trigger prostaglandin e production , cause bone marrow release of neutrophils , and induce the production of il-6 .
in fact , il-1 induction of il-6 accounts for hepatic acute phase protein synthesis and the thrombocytosis .
the finetuning of il-1mediated inflammation is revealed upon stopping and restarting il-1ra . upon cessation of il-1ra therapy , clinical signs and symptoms of disease as well as biochemical and hematological abnormalities
rebound within days and resolve upon resumption of il-1 receptor blockade ( 10 , 1416 ) . in the pascual study ,
il-1ra therapy was temporarily withdrawn in two patients due to viral - like illness , during which time the erythrocyte sedimentation rate increased , only to fall upon restarting therapy ( 7 ) .
systemic manifestations of il-1. active il-1 is secreted by many cell types including monocytes and macrophages ( center ) .
il-1 enters the circulation and triggers il-1 receptors on the hypothalamic vascular network resulting in synthesis of cyclooxygenase-2 , which causes brain levels of prostaglandin e2 to rise , thus activating the thermoregulatory center for fever production ( reference 27 ) . in the periphery ,
il-1 activates il-1 receptors on the endothelium resulting in rashes and the production of il-6 .
circulating il-6 stimulates liver hepatocytes to synthesize several acute phase proteins , which accounts for the increase in erythrocyte sedimentation rate in sojia .
il-1 also acts on the bone marrow to increase mobilization of granulocyte progenitors and mature neutrophils , resulting in peripheral neutrophilia
although sojia clearly fits with the clinical , hematological , and biochemical manifestations of the autosomal dominant autoinflammatory syndromes , and although sojia shares with these inherited diseases increased secretion of il-1 , no genetic mutations have yet been described in sojia patients that relate to il-1 secretion or any other genetic marker . however , to our knowledge no systematic examination of gene defects in the components of the il-1 inflammasome has been made in sojia .
there is no clear pattern of inheritance in sojia , and like other autoimmune diseases , the incidence is greater in families but without identification of a specific gene or mutation .
it is likely that other agents that prevent il-1mediated disease will be effective in sojia .
these are the il-1 trap , il-1specific monoclonal antibodies , il-1 receptor type i  specific monoclonal antibodies , and the caspase-1 inhibitor ( 22 ) .
it is also possible that agents that inhibit the nucleotide receptor p2x7 will reduce il-1mediated disease ( 23 ) .
if sojia is due to dysfunctional control of caspase-1 activity or the p2x7 receptor , treatment options may be targeted to the mechanism of il-1 secretion .
it is a general principal in therapeutics to target the most distal mechanism of a disease process .
several levels of control of the synthesis , processing , and secretion of il-1 have evolved , and one may assume that these function to limit inflammation .
moreover , once released , il-1 must contend with competition for receptor occupancy with the naturally occurring il-1ra , the binding and neutralization by the il-1 type ii decoy receptor ( 24 ) , and the formation of inactive complexes with constitutively secreted soluble il-1 receptor accessory protein ( 25 , 26 ) , each of which also limit il-1 responses .
although increased secretion of il-1 may account for il-1 activity in sojia , loss of control of these additional mechanisms may also be disrupted in sojia .
 a growing number of systemic inflammatory diseases characterized in part by recurrent fevers , leukocytosis , anemia , and elevated acute phase proteins are linked to interleukin ( il)-1 activity since rapid and sustained resolution is observed upon specific blockade of il-1 receptors . 
 rapid resolution of systemic and local inflammation is now also reported in systemic onset juvenile idiopathic arthritis ( sojia ) . 
 loss of control of the secretion of il-1 might be a common mechanism explaining the aberrant activity of il-1 in these diseases . 