our understanding of the interleukin-1 family ( il-1f ) has recently expanded to encompass 11 members : il-1f1-il-1f11 .
these cytokines are also termed il-1 , il-1 , il-1 receptor antagonist ( il-1ra ) , il-18 , il-36ra , il-36 , il-37 , il-36 , il-36 , il-38 , and il-33 , respectively   ( table 1 ) .
these protein molecules play a prominent role in inflammation and immune responses , acting as the first line of defense against invasive pathogenic microorganisms and physical damage .
il-38 is a novel member of the il-1f identified in 2001 by a unique high throughput cdna screening approach taking advantage of a set of oligonucleotide probes to hybridize successive arrays of human cdnas from various tissues [ 3 , 4 ] .
il-38 is the 10th member of il-1f and its receptor is termed il-1 receptor - related protein 2 ( il-1rrp2 , il-36r ) .
il-38 is an il-36 antagonist and functions as a typical receptor antagonist similar to il-1ra and il-36ra .
il-38 reduces inflammation by preventing the binding of agonist receptor ligands to il-36r , a specific receptor of il-38 .
the novel il-1-like gene , il-38 , is located in the il-1 family cluster ( except il-18 and il-33 ) on human chromosome 2q13 - 14.1 near the il-1ra gene ( il-1rn ) and il-36ra gene ( il-36rn ) .
the il-38 gene is located 49,479  bp upstream from il-1rn on the same dna strand .
the primary translated product is an il-38 precursor , 152 amino acids in length and with 16.9  kd molecular mass .
sequence analysis indicated that the il-38 protein shares 41% homology with il-1ra and 43% homology with il-36ra [ 4 , 7 ] and lower homology ( 1430% ) with il-1 and other il-1 family proteins .
in mammalian chinese hamster ovary cells , recombinant il-38 protein was synthesized into two forms , a major form at 25  kd and a minor form at 17  kd .
lin et al .   suggested that the major form of il-38 might be a result of posttranslational protein modifications , such as phosphorylation .
however , studies have shown that the il-38 protein lacks n - glycosylation and o - glycosylation consensus sites in chinese hamster ovary cells .
as is typical of the il-1 family , including il-36ra , il-36 , il-36 , and il-36 , il-38 lacks a signal peptide and caspase-1 consensus cleavage site [ 3 , 7 ] .
furthermore , the natural n terminus for il-38 is still unclear . using the multiple alignment sequence profile - based searching method ( psi - blast ) , an automated sequence and structure searching procedure ( high throughput modeling ) , and a fold recognition method ( seqfold ) , three - dimensional structural models of il-38
the il-38 structural model displays a 12--stranded trefoil structure and shares similarity with the crystal structure of il-1ra and il-1 [ 3 , 8 ] .
in addition , il-38 was categorized in the il-36 subfamily according to the length of its precursor .
thus , il-38 likely also belongs to this subfamily because it has the ability to bind to the common receptor il-36r [ 2 , 9 ] . to date , no reports have described the components and properties of il-38 .
we adopted the protparam tool [ 14 , 15 ] application to analyze the amino acid composition of il-38 , which consists of 19 amino acids .
a ( alanine ) , e ( glutamic acid ) , and l ( leucine ) were the most prevalent amino acids ( 9.2% ) in il-38 , followed by g ( glycine , 7.9% ) , p ( proline , 6.6% ) , and s ( serine , 6.6% ) . only h ( histidine ) was not present in il-38 ( figure 1 ) .
the molecular weight of il-38 is 16.9  kd and is consistent with a previous study , as predicted by protparam tool .
il-38 has a half - life of 7  h , an isoelectric point ( pi ) of 4.94 , and the molecular formula of c757h1164n198o226s9 , as analyzed by sopma ( self - optimized prediction method from alignment ) [ 15 , 16 ] .
moreover , the second structure of il-38 was composed of a -turn , random coil , -sheet , and -helix .
analysis further indicated that the random coil and -sheet were uniformly distributed in the protein chain . by multitissue first - strand cdna pcr analysis , il-38 mrna was measured in a range of tissues , including heart , placenta , fetal liver , skin , spleen , thymus , and tonsil .
il-38 was expressed mostly in the skin and in proliferating b cells of the tonsil .
however , in nonimmune tissues , such as human heart and placenta , il-38 was present at low levels , similar to other il-1f members .
some il-1f members are constitutively produced , whereas others have inducible expression , being rapidly induced by bacteria or inflammatory mediators [ 7 , 17 , 18 ] .
in 2001 , it was speculated that il-38 acted as an il-1 receptor antagonist because of its amino acid homology to the naturally occurring il-1ra and the observation that il-38 could bind to the soluble il-1 receptor type i ( il-1ri ) .
il-1ri was once considered a receptor for il-38 [ 3 , 5 ] . however , the binding affinity of recombinant il-38 is significantly lower than that of il-1ra and il-1. recently , researchers doubted whether il-1ri was a receptor for il-38 .
il-1rrp2 was regarded as an il-38-specific receptor and was also called il-36r . in a report by van de veerdonk , the combining capacity between il-38 and il-1ri , il-36r , il-18r , and il-1r accessory proteins ( il-1rap , il-1racp ) was compared , in the presence of increasing concentrations of il-38 .
il-38 bound to il-36r but did not bind to the other immobilized receptors . furthermore , il-38 binding to immobilized il-36r was comparable to il-36ra binding to the same receptor .
it was observed that increasing the concentration of il-38 resulted in increased optical density , reaching a plateau at 16.7  g / ml , a higher value than that obtained for il-36ra .
based on the binding studies , these data suggest il-38 could act by blocking the il-36r pathway .
these cytokines combine with the cell - surface receptor il-1r and induce downstream signaling , including downstream nuclear transcripts such as nuclear factor-b ( nf-b ) and activator protein-1 ( ap-1 ) . furthermore , as a feedback and adjustment mechanism ,
these signaling molecules induced the expression of cyclooxygenase , nitric oxide synthase , and other inflammatory mediators to promote the development of inflammation [ 19 , 20 ] . in line with the characteristics of il-38 and the homology of il-38 and il-36ra , it can be concluded that il-38 has a role in inflammatory disease by il-36ra pathway - related molecules ( figure 2 ) .
the biological function of il-38 is to inhibit il-36 cytokine ( il-36 , il-36 , and il-36 ) binding to il-36r , similar to il-36ra . according to its activity as a receptor antagonist
il-38 might also be related to il-1r and il-18r signaling pathways , although there is no evidence regarding its role in these specific signaling pathways .
because of its homology with other il-1f members , il-38 is thought to have the biological activity of il-1f members .
il-1 cytokines are primarily proinflammatory cytokines as they stimulate the expression of genes associated with inflammation and immunological diseases .
il-1 or il-1 binds to its primary receptor il-1ri , which recruits a second receptor subunit , il-1racp .
formation of the receptor heterodimer induces biological responses typically involving the activation of nf-b and mitogen - activated protein kinase ( mapk ) pathways .
il-1f6 ( il-36 ) , il-1f8 ( il-36 ) , and il-1f9 ( il-36 ) also activate nf-b and mapks similar to il-1 .
therefore , most molecules involved in il-1f - induced signaling , such as cytokines , chemokines , adhesion molecules , and enzymes , are mediators of inflammatory diseases [ 22 , 23 ] . il-1ra ( il-1f3 ) is the receptor antagonist of il-1 , a protein composed of two major subunits , il-1 and il-1 .
il-1ra is synthesized and released in response to the same stimuli that lead to il-1 production .
il-1ra , a potent anti - inflammatory cytokine , competitively inhibits stimulation by inflammatory mediators by binding to il-1r1 and preventing the recruitment of il-1racp .
il-1ra is associated with severe autoimmune and inflammatory diseases such as periodontitis , vaginitis , non - hodgkin 's lymphoma , gastric cancer [ 28 , 29 ] , osteoarthritis , precancerous lesions , and inflammatory bowel diseases .
deficiency of the il-1-receptor antagonist ( dira ) , caused by mutations in il1rn , can lead to an autosomal recessive autoinflammatory disease .
dira allows unopposed actions of il-1 , resulting in life - threatening excessive systemic il-1-mediated inflammation with skin and bone involvement . a study by korthagen et al . aimed to elucidate the influence of polymorphisms in il1rn on idiopathic pulmonary fibrosis ( ipf ) susceptibility and mrna expression .
polymorphisms of il1rn manifested as a variable number tandem repeat ( vntr ) , which affected il-1ra mrna expression , suggest that lower levels of il-1ra predispose to developing ipf .
il1rn may be a future novel therapeutic target with high specificity , low toxicity , and side effects for the treatment of specific diseases .
it is important to enhance our understanding of il1rn functions , such as its interaction with other genes and the influence of environmental factors on its production , to develop treatments with reduced side effects .
in addition , il1ra - deficient ( il-1ra/ ) mice , good animal models for experimental studies , spontaneously develop several inflammatory diseases , resembling arthritis , aortitis , intervertebral disc degeneration , and psoriasis in humans due to unopposed excess il-1 signaling .
the current knowledge also suggested that il-1ra , an endogenous inhibitor of il-1 , related to alcoholic steatohepatitis , liver damage , lung damage , fat mass , and aqueous - deficient dry eye in autoimmune diseases .
il-36ra ( il-1f5 ) shares 44% homology with il-1ra and is an antagonist of  il-36 , il-36 , and il-36. il-36ra has a -stranded trefoil structure , similar to other family members of il-1 , with a conserved hydrophobic core .
the mechanism of il-36ra antagonism is analogous to il-1ra by forming a functional signaling complex .
il-36ra protein starting at val-2 is fully active and inhibits il-36 , il-36 , and il-36. the a - x - asp motif is conserved in all il-1f members at the n - terminal , where val-2 of il-36ra lies in this 9-amino acid conserved sequence .
all four il-36 cytokines lack a conventional signal sequence and function as extracellular cytokines although it is unclear how they are secreted .
in addition , il-36ra antagonist activity requires removal of the n - terminal methionine present in the primary translation product .
more extensive n - terminal amino truncation of  il-36 , il-36 , and il-36 can dramatically increase their specific activities .
il-36ra plays a key role in innate and adaptive immunity by stimulating helper t - cell responses and it is associated with many inflammatory diseases .
recessive homozygous mutations in il36rn are the major cause for the development of generalized pustular psoriasis [ 4649 ] .
mutations in il36rn , including premature termination codon mutations , frameshift mutations , and substitutions of amino acid lead to incorrect folding of the il-36ra protein .
these mutations inhibit the activity of il-36ra , thus failing to antagonize il-36 signaling pathways and inducing inflammatory skin disease due to the high levels of il-36 , il-36 , and il-36. excessive il-36 levels in the skin of mice lead to symptoms to human psoriasis .
therefore , treatment with a combination of il-36ra and il-36r might improve psoriasis by inhibiting il-36 stimulation and might be an ideal treatment strategy for inflammation of human skin .
il-36ra functions as an anti - inflammatory cytokine in the brain   and enhances the hippocampal expression of il-4 .
this is a consequence of its interaction with the orphan receptor , single ig il-1r - related molecule ( sigirr)/tir8 . collectively , in vitro il-4 mrna and
protein expression in glia induced by the interaction of il-36ra and sigirr / tir8 play a critical role in its anti - inflammatory properties .
il-36 cytokines also have a significant association in the pathogenesis of rheumatoid arthritis [ 9 , 51 , 52 ] , inflammatory lung diseases [ 53 , 54 ] , obesity , bile duct occlusion disorder , and chronic glomerulonephritis .
data strongly suggest that il-36ra might be a useful treatment for il-36-related diseases . in recent years , scholars identified a novel cd4 t - cell subtype , which was different from t - helper 1 ( th1 ) and th2 cells .
these cells were named th17 cells due to the expression of il-17 and these discoveries have improved our understanding of inflammatory processes .
th17 cells are different from natural t - cell precursors , and the mature cells secrete a variety of cytokines such as il-17 and il-22 [ 57 , 58 ] .
th17 plays an important role in a variety of autoimmune diseases and has an independent regulatory mechanism for their differentiation and development .
th17 is associated with the pathogenesis of systemic lupus erythematosus , rheumatoid arthritis , multiple sclerosis , psoriasis , inflammatory bowel disease , and autoimmune thyroid diseases .
previous studies demonstrated the functions of il-38 and th17 cells by blocking the il-1r , il-18r , and il-36r pathways .
these data suggested that the influence of il-38 on th17 cells was similar to blocking il-1r and il-36r pathways , which suppressed il-17 and il-22 secretion .
consistent with binding data and the suppression of il-17 and il-22 , we suggest that il-38 has similar biological effects on th17 cells . 

il-38 gene polymorphisms are associated with psoriatic arthritis ( psa ) , ankylosing spondylitis ( as ) [ 5961 ] , and cardiovascular disease , suggesting that il-38 is strongly correlated with these inflammatory diseases .
the frequencies of th17 cells are significantly increased in the peripheral blood of patients with psa and as [ 8 , 6368 ] .
in addition , the number of th17 cells and serum il-17 levels were strongly related to systemic disease activity both at the onset and during disease progression of  psa and as .
il-38 reduced the expression of c. albicans - induced il-17 and il-22 from peripheral blood mononuclear cells ( pbmcs ) by reducing the stimulation of proinflammatory cytokines in the tissues .
a recent study reported that low concentrations of il-38 were more effective than higher concentrations in inhibiting il-17 and il-22 production because higher concentrations modestly increased il-22 .
similar to il-36ra , blocking il-38 suppressed c. albicans - induced th17 cytokine production [ 5 , 69 ] .
both il-38 and il-36ra inhibited the production of il-17 and il-22 by specifically binding to the cell surface - specific protein receptor il-36r .
however , neither il-38 nor il-36r functions as a classic receptor antagonist . in pbmcs ,
the dose - response suppression of il-38 and il-36ra by il-36-derived il-8 was not similar to that of il-1ra .
il-38 decreased the production of proinflammatory cytokines similar to il-36ra [ 5 , 70 ] .
in contrast , il-38 and il-36ra have parallel effects on the production of lipopolysaccharide - induced il-6 from dendritic cells ( dcs ) , inducing a twofold increase .
il-6 has two adverse effects on immune cells : il-6 is proinflammatory but also suppresses inflammation in tissues injured by burns or other damages . il-1ra and il-38 have a comparable dose - effect regarding their antagonist activities and function as classic receptor antagonists ; the higher the concentration of il-22 , the stronger its inhibition .
compared with il-1ra and il-38 , il-36ra does not behave as a typical receptor antagonist .
il-38 and il-36ra function as antagonists at high concentrations , but at low concentrations , they inhibit the binding of coreceptors .
thus , il-38 and il-36ra are defined as partial receptor antagonists , although they mimic the effects of il-1ra on the production of inflammatory cytokines .
il-1 and most related family members are primarily proinflammatory cytokines that induce the expression of genes associated with inflammatory diseases . only il-37 acts as an anti - inflammatory cytokine .
the binding of il-1ra and il-36ra to their receptor reduces inflammation by blocking the binding of receptor ligands .
the production of fungal - induced il-17 , il-22 , and il-36-derived il-8 was decreased by il-38 , which may play an important anti - inflammatory role in inflammatory diseases .
many articles have demonstrated that il-1ra and il-36ra are associated with arthritis and psoriasis , respectively . in addition
il-36 cytokine has significant in vivo effects on dcs and t cells in human immune responses via its role in the differentiation of inflammatory th1 cells [ 7072 ] . in conclusion
, the current knowledge supports the concept that il-38 may be closely associated with il-36-mediated inflammatory diseases .
thus far , the il-1 receptor antagonist anakinra , the soluble decoy receptor rilonacept , and the neutralizing monoclonal anti - il-1 antibody canakinumab have been approved as il-1-targeting agents for the treatment of specific diseases .
another study demonstrated the beneficial use of a monoclonal antibody directed against the il-1 receptor and a neutralizing anti - il-1 antibody in clinical trials . the il-38-related signaling pathway is poorly understood and requires further study .
the increasing knowledge of the mechanisms that regulate chronic inflammatory conditions such as rheumatoid arthritis may provide a potential strategy for the development of anti - inflammatory treatments for autoimmune diseases and establish a theoretical basis for clinical trials and drug development .
 interleukin- ( il- ) 38 is a recently discovered cytokine and is the tenth member of the il-1 cytokine family . 
 il-38 shares structural features with il-1 receptor antagonist ( il-1ra ) and il-36ra . 
 il-36r is the specific receptor of il-38 , a partial receptor antagonist of il-36 . 
 il-38 inhibits the production of t - cell cytokines il-17 and il-22 . 
 il-38 also inhibits the production of il-8 induced by il-36 , thus inhibiting inflammatory responses . 
 il-38-related cytokines , including il-1ra and il-36ra , are involved in the regulation of inflammation and immune responses . 
 the study of il-38 and il-38-related cytokines might provide new insights for developing anti - inflammatory treatments in the near future . 
1. Introduction
2. Biological Characteristics of IL-38
3. Receptor and Signaling Pathway of IL-38
4. Biological Activity of IL-38 and Related Cytokines
5. Future Perspectives