lupus nephritis ( ln ) is a major clinical manifestation of systemic lupus erythematosus ( sle ) ; it occurs in up to 50% of patients at onset of the disease and over 60% of patients during the disease .
clinical course ranges from asymptomatic urinary occult blood to nephrotic syndrome or acute kidney injury since kidney injuries in ln are so variable .
the patients of the who class iv ( proliferative glomerulonephropathy ) at initial renal biopsies show higher rate of end - stage renal failure ( esrf ) compared with those of the other classes .
the mean 50% renal survival time of class iv is 189 months in japanese patients . to understand the pathogenesis of cytokines on ln , murine models of sle
fifty percent survival is 5 - 6 months of age , and the cause of death is renal failure . in nzbxnzw mice , ln becomes apparent at 5 - 6 months of age , leading to renal failure and death at 1012 months of age .
although numerous underlying mechanisms are reported , cytokine plays a key role in disease initiation and progression .
this paper focuses on the contribution of cytokine , cytokine receptors , and intracellular signaling in ln .
the deposit of immune complexes ( ics ) has been regarded as responsible for the initiation of ln .
ic deposition activates complement cascade , leading to mesangial cell activation and proliferation . once activated , mesangial cells produce various types of cytokines and chemokines , leading to amplification of glomerular disease .
in addition to ic - mediated glomerular injury , auto - antibodies may also promote proliferation and activation in kidney resident cells .
demonstrated that anti - dna antibody induced the secretion of interleukin ( il- ) 1 , il-6 , and tumor necrosis factor ( tnf- )  in human cultured mesangial and tubular epithelial cell .
these observations suggest that renal resident cells activated by ics and/or auto - antibodies secret the cytokines , which may further amplify inflammatory processes .
they also demonstrated that anti - dna antibody induced protein kinase c activation , which is a signal pathway causing the synthesis of cytokines in human mesangial cell .
several groups showed the beneficial effects of tnf in nzbxnzw mice [ 811 ] , whereas some groups reported the adverse effects in mrl - fas mice [ 1217 ] .
the protective effect is specific to nzbxnzw strain , and the mechanism is not clear . as for the human ln , yokoyama et al
. showed that serum levels of tnf- are correlated to glomerular icam-1 expression , which is associated with endocapillary lesions in renal biopsy specimen .
summarized the reported 12 cases , who were treated with tnf blockers . in 9 out of 12 patients ,
tnf blocker therapy led to the improvement of ln and the long - term renal responses .
matsumura et al . also reported that 6 out of 8 patients showed improved urinary protein and sle activity by the anti - tnf therapy .
these data suggest that anti - tnf- therapy may have therapeutic potentials in human ln . however , some groups reported that anti - tnf- therapy in rheumatic disease induce autoantibodies formation and lead to sle including ln [ 22 , 23 ]
. we should be aware that anti - tnf- therapy could induce sle as well .
, several studies demonstrated that il-6 contributes to the production of anti - dna antibody from b cells [ 24 , 27 ] .
reported that il-6 inhibits the function of regulatory t cells in lupus model mice . in human samples ,
il-6 mrna level in peripheral blood mononuclear cells is higher in patients with active ln than that in those with inactive ln . as for the clinical therapy ,
they reported that arthritis improved all 7 patients with arthritis at base line , but there was no change of proteinuria during the study in all 5 patients with ln at the base line .
il-1 induces endothelial adhesion molecules   and increases the production of igg and anti - dna antibody from b cell   in mrl - fas mice .
anti - dsdna antibody induces il-1 production in mesangial cells , which lead to the overexpression of extracellular matrix , hyaluronan . in human ln
however , il-1 receptor antagonist therapy does not improve ln in mrl - fas mice .
several protein kinase cascades mediate the intracellular cytokine signal transduction , leading to various types of cell response , such as cell migration , proliferation , and inflammatory response .
p38 mitogen - activated protein kinase ( mapk ) is responsible for the production and signal transduction of cytokines .
we found that pharmacologic inhibition of p38 mapk significantly reduced cytokine expression and improved the renal injury in mrl - fas mice .
in addition , the inhibition of p38 mapk also reduced the number of mature dcs within injured kidney and decreased il-12 and il-23 expression on dcs ( figure 1 ) .
once inflamed renal resident cells produce cytokines and chemokines , leukocytes migrate to glomerulus and interstitium . in human ln , most infiltrating mononuclear leukocytes are t lymphocytes , with lesser numbers of macrophages ( m ) , b lymphocytes , and natural killer cells .
infiltrate m and dendritic cells ( dcs ) secrete a variety of cytokines and activate nave t cells , leading the cytokine profile towards th1 , th2 , and/or th17 .
recent studies suggest that th17 cells play a crucial role in the pathogenesis of ln .
zhang et al . demonstrated that il-17-producing cd3 cells from lupus prone mice induce nephritis when transferred to nonautoimmune , lymphocyte - deficient rag-1 mice .
steinmetz et al . showed that cxcr3 , which is expressed on th1 and th17 cells , deficient lupus prone mrl - fas mice ameliorate ln accompanied by the reduction of interferon ( ifn)- and il-17 producing t cells .
furthermore , il-23 receptor b6/lpr mice are protected from the development of ln , followed by the decrease of il-17-producing t cells .   in human ln
reported that cd4cd8 double - negative t cells produce il-17 and infiltrate the kidneys in ln patients .
interestingly , double - negative t cells have been reported as a major source of il-17 in mrl - fas mice as well . 
					 
il-12 mrl - fas mice are protected from ln followed by the reduced production of ifn- .
moreover , ifn- receptor mrl - fas mice showed the decreased renal pathology and extended survival .
in contrast , the role of type i ifn ( ifn-/ ) , which is classically thought to induce th1 type inflammation , is equivocal .
the administration of ifn- accelerates the development of lupus in lupus - prone mice [ 46 , 47 ] .
moreover , type i ifn receptor ( ifnar ) nzbxnzw is protected from ln . as opposed to this study ,
hron and peng reported that ifnar mrl - fas mice showed increased lymphadenopathy , autoantibody production , and ln .
of note , schwarting et al . reported that the ifn- therapy reduces the activity of ln in mrl - fas mice .
these results indicate the different role of ifn- and ifn- in ln though ifnar is the common receptor for both ifns . supporting this notion , satchell et al .
reported that ifn- had an effect on barrier properties , increasing electrical resistance across monolayers of either glomerular endothelial cells or podocytes and decreasing transmonolayer passage of albumin .
il-18 , which is a strong inducer of ifn- , is upregulated in mrl - fas mice .
interestingly , docosahexaenoic acid in fish oil decreased serum levels of il-18 and attenuated lupus nephritis in nzbxnzw mice .   in human ln ,
they also demonstrated that ifn-/il-4 ratio in peripheral blood cd4 cell was correlated with pathological activity index .
yokoyama et al . revealed that serum level of ifn- is related to proliferative and active lesions , and the level is decreased by methylprednisolone pulse therapy .
chan et al . reported the correlation between glomerular expression of the th1 transcription factor ( t - bet ) , ifn- , and il-2 with serum c3 , c4 and anti - double - strand - dna antibody level .
tucci et al . demonstrated the il-18 expression within glomeruli in patients with severe ln .
charles et al . revealed that autoreactive ige and il-4 are essential for lupus model mice and sle patients .
they showed that activated basophils secret il-6 and il-4 , which promote th2 response and b cell activation , resulting in autoantibodies production [ 62 , 63 ] .
il-27 receptor mrl - fas mice showed membranous glomerulonephritis with the predominance of th2 systemic reaction . in lupus patients with who type v ( membranous nephropathy ) , ifn-/il-4 expression ratio was lower in peripheral blood t cell , whereas ifn-/il-4 expression ratio was higher in those with who type iv ( proliferative glomerulonephropathy ) .
furthermore , th2 cytokine dominance is also reported in the kidney tissue from the patients with who type v .
originally , th2 cells and antigen - presenting cells have been reported as a source of il-10 .
however , recent reports show that th1 cells and th17 cells in addition to th2 cells produce il-10 [ 6669 ] .
ishida et al . reported that anti - il-10 therapy delayed the onset of lupus nephritis in nzbxnzw mice .
interestingly , they showed that anti - il-10 therapy increased the serum levels of tnf- , which contributed to the protection from autoimmunity .
also described that anti - il-10 therapy reduced proteinuria in human ds - dna ab - induced lupus model mice .
continuous overexpression of low levels of il-10 delayed the production of autoantibodies and decreased the severity of ln .
these differences may be related to the mice strain , disease models , and/or the amount of il-10 expression . in sle patients , anti - il-10 therapy ameliorates skin and joint lesions in all 6 patients
. however , the effect of anti - il-10 therapy on ln is not clear in this study .
cytokine is upregulated by the immune deposits and/or autoantibodies in disease initiation phase , leading to inflammatory cytokine / chemokine expression and leukocyte infiltration and activation .
activated leukocytes produce cytokines , which amplify the inflammatory response . then , sustained cytokine production by multiple triggers is associated with progression of ln .
thus , cytokine is essential from the initiation to progression phase of ln ( figure 2 ) .
. however , sufficient evidence is not yet available to clarify the efficacy of anticytokine therapy for human ln .
 lupus nephritis ( ln ) 
                   is a major clinical manifestation of systemic 
                   lupus erythematosus ( sle ) . 
 although numerous 
                   abnormalities of immune system have been 
                   proposed , cytokine overexpression plays an 
                   essential role in the pathogenesis of ln . in the 
                   initial phase of the disease , the 
                   immune deposits and/or autoantibodies induce 
                   cytokine production in renal resident cells , 
                   leading to further inflammatory 
                   cytokine / chemokine expression and leukocyte 
                   infiltration and activation . 
 then , infiltrate 
                   leukocytes , such as macrophages ( m ) and dendritic cells ( dcs ) , secrete a variety of 
 cytokines and activate nave t cells , leading the cytokine 
 profile towards t helper ( th)1 , th2 , and/or th17 . 
 recent studies 
 revealed these inflammatory processes in experimental animal 
 models as well as human ln . 
 the cytokine targeted intervention may 
 have the therapeutic potentials for ln . 
 this paper focuses on the 
 expression of cytokine and its functional role in the pathogenesis 
 of ln . 
1. Introduction
2. The Role of Cytokines in the Disease Initiation Phase
3. The Role of Cytokine in the Disease Amplification/Progression Phase
4. Conclusion