disturbed immune - mediated inflammatory reactions are involved in the pathogenesis of psoriasis and its comorbidities . there is evidence that the combined epidermal and microvasculature hyperplasia results from a response to the immune cell infiltrate present in the skin [ 24 ] . in recent years , some specific inflammatory cytokine pathways have represented promising or established therapeutic targets [ 16 ] . in particular , biologicals directed to tumor necrosis factor ( tnf)- , interleukin ( il)-12 , il-23 , as well as cd4 + t helper ( th ) 1 and th17 effector cells fitted with the psoriasis pathobiology [ 7 , 8 ] . il-12 is a heterodimeric protein consisting of the two disulfide - linked , glycosylated p35 and p40 subunits . this cytokine is secreted by dendritic antigen - presenting cells in response to inflammatory stimuli or infections . the il-12 cytokine activates natural killer ( nk ) and t - cell responses , including naive cd4 + t - cell differentiation toward the cd4 + th1 phenotype [ 911 ] . the heterodimeric il23 cytokine contains the identical p40 subunit disulfide - linked to a p19 subunit . following activation by il-6 and transforming growth factor ( tgf)- , 
  il-23 in concert with tnf supports the development of th17 cells [ 913 ] . the p40 subunit of both il-12 and il-23 binds to the il-12 receptor-1 ( il-12r1 ) [ 14 , 15 ] . these distinct binding processes account for the cytokine biological specificities [ 11 , 14 , 15 ] . thus , despite some structural similarities between il-12 and il-23 , they control distinct immunological pathways . il-12 promotes the development of th1 populations producing interferon ( ifn)- , tnf- , and il-2 . by contrast , il-23 in combination with il-21 and tgf drives the development of cd4 + th17 populations producing il-17 , il-22 , tnf- , and il-1 . psoriasis apparently results from the activation of an abnormal immune response leading to excessive keratinocyte proliferation and global epidermal thickening . in particular , cytokines produced by th1 and th17 cell populations play a pivotal role in the development and maintenance of psoriatic lesions [ 1315 , 1719 ] . the p40-containing cytokines are involved in the psoriasis pathogenesis   because there is overexpression of the il-12p40 and the il-23p40 in psoriasis plaques [ 2022 ] . gene polymorphisms encoding the shared p40 subunit or one of the components of the il-23 receptor ( il-23r ) complex are linked to psoriasis . an uncommon il-23r coding variant protecting against crohn 's disease appears to confer protection against psoriasis [ 24 , 25 ] . gene expression levels of il-12p40 , ifn- , and il-23p49 are raised in psoriatic lesions [ 21 , 23 , 26 ] . both il-17 and il-22 promote epidermal proliferation and remodelling , through activation of the keratinocyte transcription factor stat3 , and upregulate keratinocyte host defence proteins , including human -defensin ( hd)-2 [ 19 , 27 ] . ifn- in concert with stat 1 activates keratinocytes to upregulate major histocompatibility complex class ii , while both intracellular adhesion molecules ( icam ) and tnf contribute to the development of psoriatic plaques [ 1 , 18 , 28 , 29 ] . in addition , il-23 drives monocytes to differentiate into dendritic cells . this might account for the presence of many factor xiiia+ dermal dendrocytes . th1 and th17 cells are involved in the psoriasis pathobiology following secretion of a series of inflammatory cytokines , including ifn- , il-17 , and il-22 , that in turn activate keratinocytes to proliferate and secrete additional proinflammatory mediators . the il-12 and il-23 cytokines produce a downstream impact on th1 and th17 cell activation , as well as keratinocyte triggering . accordingly , any therapeutic agent designed to block il-12 and il-23 likely abates the upregulation of ifn- , il-17 , and il-22 by both th1 and th17 cells . th17 cells play a central role in the development of psoriasis [ 2 , 31 ] . these cells conduct immunosurveillance in the epidermis and secrete il-17a , il-17f , and il-22 . in psoriatic lesions , the proinflammatory il-17 leads to the production of other cytokines and angiogenic factors , committing naive t cells to the th17 lineage and creating a positive feedback loop for th17 inflammation . il-22 acts on keratinocytes through the il-22 and il-10 receptors , resulting in hyperproliferation and altered keratinocyte maturation leading to the typical acanthosis of psoriatic lesions [ 33 , 34 ] . il-17 and il-22 produce a synergist stimulation of keratinocytes to be resistant to microbial infection through the expression of antimicrobial peptides . some th17 cells produce il-17 only , while th22 cells solely produce il-22 [ 35 , 36 ] . thus , no differentiation was possible between the presence of il-12 and il-23 [ 3740 ] . a pivotal study showed rna upregulation of the p40 subunit shared by il-12 and il-23 and of the il-23p19 subunit , but not an increased expression of the il-12p35 subunit . such finding suggested that il-23 was more involved in the maintenance of psoriatic lesions than il-12 . additionally , il-23 is a more potent activator of keratinocyte proliferation than il-12 [ 39 , 40 ] . the psoriasis immunopathogenesis has provided new therapeutic options in recent years . among recent breakthroughs , ustekinumab ( stelara , janssen pharmaceutica , beerse , belgium ) is a fully human monoclonal antibody of the igg1 class . it is directed to the shared p40 subunit of both il-12 and il-23 [ 4143 ] . thus , the drug neutralizes the bioactivities of both cytokines by blocking interaction with the il-12r 1 cell surface receptor . the pharmacological characteristics and both the clinical efficacy and tolerability of ustekinumab are clearly proven in patients with chronic moderate to severe plaque psoriasis , including subjects with psoriatic onychopathy and psoriatic arthritis [ 8 , 4346 ] . il-23 messenger rna expression is significantly higher in lesional skin of psoriatic patients as compared with healthy skin in the same patients [ 5 , 38 ] . il-23 secretion by monocytes and mature dendritic cells derived from patients with psoriasis is unusually high . this cytokine promotes survival and proliferation of th17 cells [ 4751 ] . as a result , th17 cytokines , such as il-17 , stimulate keratinocyte proliferation enabling further stimulation of keratinocyte proliferation in psoriatic lesions [ 6 , 29 ] . the therapeutic efficacy of ustekinumab is obtained after il-12 and il-23 inhibition leading to the abated expression of cell surface markers associated with skin homing ( cla ) , activation of anti - inflammatory cytokines including il-5 , and inhibition of the secretion of the proinflammatory cytokines ifn , il-2 , il-8 , il-10 , il-17a , and tnf. a reduction in cd4 + th cells and nk cells was reported after a single dose of ustekinumab . recent clinical trials conducted in humans emphasized the crucial role of th17 cells boosted by il-23 in the immunopathogenesis of several other inflammatory skin diseases , including allergic contact dermatitis , systemic scleroderma , and sarcoidosis [ 5258 ] . in addition , the il-23/th17 axis appears to play a prominent role in the development of other diseases with possible cutaneous involvement . these include systemic lupus erythematosus [ 59 , 60 ] , rheumatoid arthritis , inflammatory bowel disease , and behet disease . considering the major role of il-23-dependent th17 cells in several skin diseases , future indications for il-23 pathway inhibitors will probably emerge in a field much more broader than currently documented . at present , the advent of biological therapies has already revolutionized the treatment of autoimmune diseases beyond psoriasis , including autoimmune arthritides , and inflammatory bowel diseases . . the long - term limitations of conventional systemic psoriasis therapies because of the potential for severe renal , hepatic , and pulmonary adverse events have led to the development of biotherapies . these agents alter specific immunologic pathways involved in the development of the disease , including some cytokine productions . at present , it appears that il-23 is more involved than il-12 in the pathogenesis of psoriasis . ustekinumab is a monoclonal antibody to the common p40 subunit shared by il-12 and il-23 . other conditions including psoriatic arthritis , crohn 's disease , and some other autoimmune diseases are expected to become recognized indications for the drug .
psoriasis is a chronic relapsing immunoinflammatory dermatosis that is commonly associated with systemic comorbidities . 
 the pathogenic importance of interleukin ( il)-12 and il-23 is beyond doubt , as well as the involvement of t helper cells ( th)1 and th17 cells . 
 there is upregulation of the p40 subunit shared by il-12 and il-23 and of the il-23 p19 subunit , but not an increased expression of the il-12 p35 subunit . 
 this indicates that il-23 appears more involved than il-12 in the pathogenesis of psoriatic plaques . 
 ustekinumab is a fully human monoclonal antibody of the immunoglobulin ( ig ) g1 class targeting the p40 subunit common to both il-12 and il-23 , thus inhibiting both il-12 and il-23 receptor - mediated signalling . 
 ustekinumab is part of the recent biologic therapies active in psoriasis , autoimmune arthritides , and inflammatory bowel diseases .