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Clin Exp Immunol. 2008 Nov; 154(2): 247–254.
PMCID: PMC2612719

Overexpression of interleukin-12 and T helper 1 predominance in lupus nephritis


Imbalance of cytokine homeostasis is a prominent feature of both experimental and human systemic lupus erythematosus (SLE). Because interleukin (IL)-12 promotes interferon (IFN)-γ production leading to polarization of peripheral cells toward a T helper (Th) 1 phenotype, we investigated its role in lupus nephritis (LN). Soluble Th1 and Th2 cytokines were measured by enzyme-linked immunosorbent assay (ELISA) in sera and urines of SLE patients and controls. Th1/Th2 peripheral lymphocyte polarization was determined by flow cytometry. Glomerular accumulation of IL-12 was evaluated by immunohistochemistry, whereas urinary IL-12 was evaluated by ELISA. Higher serum IL-12 levels in SLE were associated with LN, whereas IL-4 was unrelated to the renal damage. Peripheral cells from LN patients showed a Th1 phenotype with a high IFN-γ expression that paralleled the severity of renal damage. IL-12 was present within glomerular mononuclear cells in classes IV and V LN, and its accumulation was correlated strongly with urinary levels. IL-12 overexpression in SLE may contribute to the development of LN. Both serum and urinary IL-12 elevation reflect its glomerular production and parallel Th1 polarization of peripheral T cells and high IFN-γ production. In SLE patients, IL-12 measurement may thus be predictive of the development of LN.

Keywords: IL-12, LN, SLE, Th1 cytokines


Lupus nephritis (LN) is a major complication of systemic lupus erythematosus (SLE) that aggravates both its morbidity and mortality. It is mediated by the glomerular deposition of immune complexes that promote a cascade of inflammatory events leading to severe tissue damage. Anti-dsDNA antibody deposition is an early event in LN and is followed by local production of both cytokines and chemokines that trigger glomerular inflammation and ultimately drive the irreversible renal damage [13], although the mechanism(s) of their pathogenic role is uncertain.

Disruption of T helper (Th) 1 and Th2 cytokine homeostasis is a peculiar feature of human and experimental LN [46]. SLE is regarded currently as a Th2-driven disease [79]. Recent findings, however, suggest that Th1 cytokines exert the major nephritogenic role [10].

Interleukin (IL)-12 is a 70 kDa heterodimer (IL-12p70) produced by macrophages and dendritic cells (DC). In conjunction with IL-18, it promotes interferon (IFN)-γ production and the proliferation or differentiation of naive T cells [11]. Serum IL-12 levels are high in MRL/lpr mice that develop spontaneously a lupus-like syndrome resembling human SLE [12], whereas treatment of NZB/NZW-F1 mice with recombinant IFN-γ exacerbates proteinuria, glomerulonephritis and Th1 cytokine overproduction [13]. Similarly, increased serum and glomerular IFN-γ and IL-18 levels have been demonstrated in patients with active LN, in parallel with Th1 polarization of peripheral T cells [14,15]. Therefore, the role of IL-12 is controversial, as its direct participation in the development of LN has not been proved definitively [6,1618].

This paper illustrates our investigation of the functional role of IL-12 in LN through the measurement of its serum and urinary levels in patients with SLE. In addition, its glomerular accumulation was evaluated in parallel with peripheral T cell phenotype characterization. We found that high serum levels of IL-12 and IFN-γ were related linearly to laboratory parameters of renal dysfunction. IL-12 was also detectable in the glomeruli of severe LN patients in parallel with high urinary content. It may thus be predictive of LN, and its functional blockade could represent a potential goal for the treatment of LN itself.

Material and methods

Study population

Whole blood, serum and urine samples from 150 SLE patients [≥ 4 American College of Rheumatology criteria][19,20] and 69 matched normal controls were enrolled at the Department of Rheumatology of the University of Florida and at the Department of Internal Medicine and Clinical Oncology of the University of Bari. Informed consent was obtained from all subjects and the study was approved by the Ethical Committees of both clinical centres. All patients were free from other chronic renal diseases. Detailed demographic data and laboratory parameters including serum creatinine, albumin, total protein, urinary microalbumin (MAU), proteinuria and anti-dsDNA antibodies by Crithidia luciliae were recorded previously. SLE patients were grouped with regard to the presence (group A; n = 52) or absence (group B; n = 98) of LN and the controls were included in group C. Diagnosis of LN was confirmed by biopsy and the class of nephritis was assessed according to both the World Health Organization (WHO) classification and the revised classification of LN [21,22]. Patients of group A were divided into subsets in relation to the WHO classes as follows: subset II (class II; n = 4), subset III (class III; n = 7 including two patients with combined classes V–III), subset IV (class IV; n = 25 including six patients with combined classes V–IV) and subset V (class V; n = 16). The female/male ratio was 10:2 and median age of SLE patients was 37·1 ± 10·1 years with no differences with regard to age, sex and race. Demographic data are summarized in Table 1.

Table 1
Demographic data.

Cytokine enzyme-linked immunosorbent assays

A sandwich enzyme-linked immunosorbent assay measured IL-12p70/p40 and IL-4 in both sera and urine, whereas both IL-23p19 (Abcam, Cambridge, UK) and IFN-γ were measured in sera only. Both sera and urine were stored at −80°C until thawing. Urine was spun at 200 g for 5 min to remove cells and esterase-positive leucocyte samples were discarded. Urine and sera samples were diluted 1:10 and 1:30 respectively. Briefly, 96-well Nunc plates were coated overnight at 4°C with specific purified mouse anti-human cytokine monoclonal antibody (mAb) (Pharmingen, San Diego, CA, USA). A biotinylated anti-cytokine antibody (Pharmingen) was used as secondary antibody and the streptavidin–alkaline–phosphatase diluted 1:1000 (Southern Biotechnology, Birmingham, AL, USA) was added. The reaction was developed with an o-phenyldiamine chromogen solution (Sigma, St Louis, MO, USA) and the relative optical density was measured at 405 nm using a microplate reader (Molecular Devices, Sunnyvale, CA, USA). Data were analysed with Softmax software and the results were related to the standard curve obtained by using recombinant cytokines. Urinary cytokine levels were corrected for urinary volume by measurement of urinary creatinine. Values were expressed as the cytokine/creatinine ratio and shown in the text and figures as units.

Cell culture and flow cytometry

Aliquots of whole blood diluted 1:1 with serum-free RPMI-1640 were stimulated with both 25 ng/ml phorbol myristate acetate (PMA; Sigma, Milan, Italy) and 1 µg/ml ionomycin (Sigma) for up to 12 h at 37°C in 5% CO2, and for a further 3 h with GolgiStop solution (Pharmingen) to enhance the sensitivity of cytokine detection. Supernatant was collected for soluble cytokine measurement. Non-adherent cells were fixed and permeabilized. The following mAbs were used: anti-CD3, -CD4, -CD8, -CD19, -IFN-γ and -IL-4 (Pharmingen) and analysed by a six-colour FACScanto cytometer using the fluorescence activated cell sorter (FACS)Diva software (Becton Dickinson, San Jose, CA, USA). A total of 30 000 events were counted and cytokine expression was analysed gating on CD3+/CD4+ cells. Mouse IgG2a and IgG1 were the isotypic controls.


Frozen specimens from renal biopsies of the patients and normal subjects with persistent proteinuria without renal findings were studied to define the expression of IL-12. Briefly, after blocking with 2% horse serum, sectionswere incubated overnight with anti-human IL-12p70 mAb (Pharmingen) at appropriate concentrations. Binding of the secondary biotinylated horse anti-mouse IgG was detected using the Vectastain ABC system (Vector Laboratories, Burlingame, CA, USA). Endogenous peroxidase activity was blocked with 3% H2O2for 30 min; 3,3′-diaminobenzidine was then added for 10 min and nuclei were counterstained with haematoxylin (DakoCytomation, Milan, Italy). Mouse IgG1 was used as isotypic control, whereas the specificity of glomerular IL-12p70 accumulation was proved using a mouse anti-rabbit IL-12p70 mAb to rule out the interference due to the tubular and interstitial staining observed in some sections. The number of glomerular-positive cells was expressed as mean value/glomerular cross section (gcs). Staining was evaluated by light microscopy.

Statistical analysis

Differences of cytokine levels were analysed by both Mann–Whitney U- and one-way analysis of variance (anova) tests. Bonferroni correction was applied to validate differences in cytokine levels and significance was set at P < 0·0167 (P < 0·05/3). In addition, the difference among LN subsets was evaluated by one-way anova followed by a post hoc Newman–Keuls test for multiple comparisons of means. A value of P < 0·05 was considered statistically significant. The correlation of serum IL-12p70 with serum IFN-γ, urinary IL-12p70, MAU, total urinary protein and anti-dsDNA was assessed by Spearman's rank correlation analysis with P < 0·05 as the significance cut-off.


Serum IL-12p70 correlates with LN

Figure 1a shows the serum levels of IL-12p70, IFN-γ and IL-4 in SLE (groups A and B) and controls (group C). IL-12p70 and IFN-γ were higher in SLE (462·0 ± 637 pg/ml and 509 ± 562 pg/ml respectively) than in group C (79·9 ± 67 and 74·9 ± 61 pg/ml respectively, P < 0·0001 in both instances), in parallel to IL-4 (890·2 ± 677 and 352·1 ± 298 pg/ml respectively; P < 0·0001). Further investigations (Fig. 1b), however, showed that IL-12p70 levels were higher in group A (730·2 ± 698 pg/ml) than in group B (342·7 ± 494 pg/ml, P < 0·0001) in parallel to IFN-γ (679·7 ± 765 and 257·3 ± 340 pg/ml respectively; P < 0·0001 in both instances) whereas IL-4 was increased in group B (1146 ± 694 versus 634·4 ± 532 pg/ml; P < 0·05).

Fig. 1
Correlation of serum cytokines with occurrence of nephritis in systemic lupus erythematosus (SLE). Measurement of T helper 1 (Th1) and Th2 cytokines by enzyme-linked immunosorbent assay (a) revealed higher concentrations (P < 0·0001) of ...

Moreover, the correlation of serum IL-12p70 and IFN-γ with LN class was investigated. As shown in Fig. 1c, the highest IL-12p70 content was found in subsets IV (853 ± 967 pg/ml; P < 0·05) and V (659·8 ± 460 pg/ml; P < 0·05), followed by subset III (445 ± 150 pg/ml) and subset II (348 ± 137 pg/ml). Similarly, serum IFN-γ was higher in subset IV (713·2 ± 181 pg/ml), whereas the values of the other subsets were similar to those of group B. Lastly, a positive correlation between serum IL-12p70 and IFN-γ (Fig. 1d; P < 0·0001, r = 0·5912) pointed to their concurrent production in LN, whereas Fig. 1e shows the inverse correlation between serum IL-12p70 and IL-12p40. This may, potentially, exclude the inhibitory effect of the p40 chain on the activity of p70.

Peripheral T cells express uniformly the Th1 phenotype in LN

Next, flow cytometry was employed to determine the Th1/Th2 profile of the peripheral T cells and their ability to produce different cytokines in vitro. As shown in Fig. 2, the controls (Fig. 2a) and group B (Fig. 2b) displayed a similar Th1/Th2 profile (ratio: 0·3 and 0·2 respectively) with increased percentage of CD4+/IL-4+ cells and defective CD4+/IFN-γ+ cells (on average 24·4% and 45·4% versus 13·1% and 6·8%). By contrast, the group A cells displayed a Th1 profile characterized by high IFN-γ expression that paralleled the severity of renal damage. In detail, patients in subsets IV (Fig. 2d) and V (Fig. 2e) displayed high IFN-γ expression (on average 54·2% and 56·4%) and a prevalent Th1 profile (ratio: 45·1 and 12·8 respectively), whereas the phenotype of those in subset III (Fig. 2c) was similar to that of groups B and C. Figure 2f shows the individual Th1/Th2 ratio of IFN-γ+/IL-4+ cells from patients and controls. These results suggest that patients with LN display an imbalance towards a Th1 phenotype that parallels the severity of renal damage. Subset IV showed a high Th1/Th2 ratio (29·6 ± 12·3) compared with both subsets V (14·9 ± 10·2; P < 0·05) and III (7·1 ± 3·8; P < 0·0001), the values of which were almost similar to both groups B (5·8 ± 2·9) and C (4·6 ± 2·4).

Fig. 2
Flow cytometry characterization of peripheral interferon (IFN)-γ+/interleukin (IL)-4+ cells in systemic lupus erythematosus (SLE) patients with and without lupus nephritis (LN). (a–e) Analysis revealed the expansion of IFN-γ+cells ...

Because over-expression of IL-12p70 may induce T cells to produce IFN-γ, Th1 and Th2 cytokines were measured in the supernatants of cultured cells. As shown in Fig. 2g, group A cells produced substantial amounts of IL-12p70 and IFN-γ (514·2 ± 154 pg/ml and 581 ± 211 pg/ml) and low IL-4 (463 ± 45 pg/ml) compared with group B (211 ± 44 pg/ml and 289 ± 91 pg/ml and 809 ± 207 pg/ml; P < 0·05), while observation of the highest levels of soluble IL-12p70 (640·3 ± 70 pg/ml and 440 ± 90 pg/ml) and IFN-γ (801·8 ± 90 pg/ml and 580 ± 50 pg/ml) in subsets IV and V indicated that peripheral T cells tend to polarize toward the Th1 phenotype.

Glomerular expression of IL-12p70 is up-regulated in LN

Immunohistochemistry of glomerular expression in LN biopsies to evaluate renal IL-12p70 production revealed a prevalent expression in the glomeruli of subsets IV and V (Figs 2b, c), whereas it was weak or absent in subsets III (Fig. 2a) and II. As expected, IL-12p70 was not detected in class I LN specimens, nor in the normal control. With regard to the location of the glomerular cytokine expression, IL-12p70 was prevalent in infiltrating mononuclear cell population. Correlative analysis of the number of glomerular IL-12p70+ cells and the LN grade showed that IL-12p70+ mononuclear cells were higher in classes IV and V (20·5 ± 8 cells/gcs and 12·3 ± 2 cells/gcs respectively) compared with class III (3·1 ± 0·5 cells/gcs; P < 0·05 in both instances).

Urinary IL-12p70 content correlates with LN grade

Urinary levels of IL-12p70 in LN patients were determined to investigate for a relationship between glomerular accumulation and increased urinary secretion. Urinary IL-12p70 was higher in SLE compared with the controls (213·8 ± 354 units versus 68·8 ± 40 units), although a low difference was demonstrated. However, as shown in Fig. 3d, the analysis of urinary IL-12p70 production in relation to presence of LN revealed that the difference in SLE population was attributable mainly to patients of group A, who produced high urinary IL-12p70 (268 ± 270 units) than those of group B (63·1 ± 64 units, P < 0·0001). In addition, urinary IL-12p70 was not influenced by urinary IL-12p40 levels that were low in both controls and patients independently by LN. As shown in Fig. 3e, investigation of the correlation between urinary IL-12p70 levels and LN class revealed that levels were highest (P < 0·05) in subset IV patients (366 ± 324 units), followed by subsets V (285 ± 296 units) and III (93 ± 51 units). In addition, a correlation between renal disease activity and urinary IL-12p70 production occurred in subset IVa (467 ± 342 units; P < 0·05) that showed a major glomerular accumulation of IL-12p70+ cells (23·1 ± 7·8 cells/gcs) with respect to both subset Iva–c and IVc (16·8 ± 5·2 cells/gcs and 15·0 ± 8·7 cells/gcs respectively). Patients of subset III showed urinary and glomerular IL-12p70 levels unrelated to the histological disease activity. Furthermore, urinary IL-12p70 in group A was correlated with total urinary protein (P < 0·05, r = 0·4244), MAU (P < 0·05, r = 0·3912) and anti-dsDNA autoantibodies (P < 0·05, r = 0·4816). The measurement of urinary IL-4 (data not shown) in groups A (90 ± 30 units) and B (79 ± 44 units) revealed values similar to group C (70 ± 31 units). Lastly, a correlation between serum and urinary IL-12p70 was demonstrated (r = 0·475; P < 0·0001). Urinary IL-12p70 elevations may thus reflect glomerular IL-12p70 production in LN.

Fig. 3
Glomerular and urinary interleukin (IL)-12p70 expression in lupus nephritis (LN). The upper panel illustrates glomerular expression in biopsy specimens from subsets III (a), IV (b) and V (c). Glomerular IL-12p70 accumulation parallels LN severity: subset ...


Contrary to the predominant interpretation of SLE as a Th2-driven disease, recent studies suggest that Th1 cytokines are involved in the induction and progression of LN [12,23]. The results of this study indicate that increased IL-12 production is associated closely with renal disease in parallel with Th1 polarization and increased IFN-γ solubilization in vitro. In addition, increased urinary IL-12 apparently reflects both its serum and its glomerular accumulation. IL-12 may thus be a pathogenetic mediator of renal failure in SLE.

The role of IL-12 is still uncertain. Its elevated serum levels in SLE patients with serositis was found to be unrelated to disease activity and renal injury [6,18]. These studies, however, included few patients and lacked racial and genetic homogeneity [17,24,25]. Our results show that both Th1 and Th2 cytokines are elevated in SLE, whereas serum IL-12 is correlated with the presence and severity of LN.

The biologically active form of IL-12, namely IL-12p70, is produced mainly by DC and formed of disulphide-linked p35 and p40 chains. The p40 monomer may displayprofound inhibitory effect on IL-12p70 functions in experimental SLE. High serum p40 in parallel to low p70 levels were demonstrated in human SLE and correlated with disease activity [26,27]. This partly explains the low IL-12p70 levels demonstrated in different studies. We therefore measured both subunits and found that they were correlated inversely. This ruled out the inhibition of IL-12p70 by p40. In addition, IL-23 shares p40 subunit with IL-12, although it is not implicated in the Th1 immune response and promotes the development of Th–IL-17-producing cells [28]. We measured the IL-23p19 subunit, the levels of which were low both in patients and controls, thus excluding its influence in IL-12p70 measurement.

It has been suggested that serum levels of cytokines may not reflect actual inflammation as their functional state is that of complexed molecules bound to soluble receptors. We have addressed this question by evaluating the in situexpression of IL-12p70 in biopsies from LN patients. Glomerular IFN-γ+ and IL-12p70+ cells have been demonstrated in MRL/lpr mice, whereas IL-12-deficient mice displayed mild, delayed nephritis with reduced proteinuria. Because Th1 cytokines, such as IL-18, promote renal damage in experimental and human LN, Th1 overexpression may be responsible primarily for the development and propagation of renal damage and other SLE-related complications. We found IL-12p70+ cells in the glomeruli of classes IV and V patients. They were located mainly in the mononuclear cells surrounding the glomeruli, and were almost absent in patients with minor glomerular lesions. As both macrophages and DC are major producers of IL-12, we speculate that its local renal production may contribute to its elevated circulating levels.

The predominance of Th1+ cells in nephritic kidneys with imbalance of the peripheral IFN-γ : IL-4 ratio has been proposed as promoter of renal tissue damage [29]. The severity of LN depends on activated T cells and macrophages that secrete a variety of cytokines and inflammatory molecules within the kidney. Several studies have postulated that circulating cells may reflect local inflammation poorly, although IFN-γ overexpression may lead to renal failure. However, a cytokine gene expression profile of peripheral cells from patients with SLE at different clinical activity levels has identified recently a correlation between their Th1 phenotype and disease activity with no reference to LN [30]. On the other hand, the association between the peripheral blood Th1 : Th2 ratio and the histological activity index has been demonstrated previously [29], as well as the presence of glomerular osteopontin as a functional trigger for IL-12 production in an autocrine feedback loop [31]. We demonstrated that peripheral T cells from LN patients skew to a Th1 phenotype with high IFN-γ expression that parallels the severity of LN, whereas a normal IFN-γ/IL-4 ratio such as that of patients without LN was evident in classes II and III. In keeping with this finding, the percentages of peripheral IFN-γ+ T cells and glomerular IL-12+ cells were correlated positively, while their stimulation induced high solubilization of both IL-12p70 and IFN-γin vitro.

Because glomerular accumulation of IL-12p70+ cells apparently reflected both serum IL-12p70 levels and IFN-γ overexpression by T cells, further experiments evaluated urinary IL-12p70 in patients with LN.

The proliferative form of LN is characterized by an influx of IFN-γ+ macrophages into glomeruli. These cells produce neopterin, a cytokine-inducible molecule present in urine during infectious diseases and autoimmune disorders generated by the biopterin biosynthetic pathways in humans, whereas it is not produced by B, T or natural killer (NK) cells [3235]. Therefore, neopterin may identify excess serum and cellular IFN-γ as a mirror of glomerular inflammation. Other urinary molecules have been proposed as predictive marker of LN. IL-6 increases in LN and is correlated with mesangial proliferation, and urinary monocyte chemoattractant protein (MCP)-1 is also increased in proliferative LN [36,37]. Lastly, IFN-γ and IL-2 mRNA expression has been demonstrated in urinary sediment of patients with active LN [30].

Urinary IL-12p70 levels are higher in SLE patients with LN and correlate with its severity and histological activity in those with proliferative LN. Thus, urinary IL-12p70 production reflected its major glomerular accumulation in these patients. Moreover, urinary IL-12p70 is correlated with proteinuria and MAU and there is a positive association between glomerular and urinary IL-12p70. For this reason, urinary IL-12p70 can be regarded as an indicator of renal dysfunction in SLE.

Participation of IL-12 and IFN-γ in renal pathology is indicated by several experimental models. IFN-γ drives nephritis in MRL/lpr mice in conjunction with IL-12 and IL-18, while IFN-γ-receptor signalling is essential for initiation and acceleration of renal destruction [38]. Furthermore, IFN-γ up-regulates major histocompatibility complex class II antigens, and promotes the recruitment of inflammatory cells as well as the overexpression of integrins and adhesion molecules [12,39,40]. IL-12 also promotes renal damage in lupus-prone mice by fostering the accumulation of intrarenal IFN-γ T secreting cells and macrophages, whereas administration of IL-12 accelerates both glomerulonephritis and anti-dsDNA antibodies production in NZB/WF1 mice. On the other hand, treatment with recombinant anti-IL-12 apparently ameliorates renal disease [41].

In conclusion, our findings suggest that IL-12 triggers intrarenal inflammation and promotes a cytokine imbalance of peripheral cells toward a Th1 phenotype, and that urinary IL-12 are effective indicators of both disease activity and severity of the glomerular inflammation. IL-12 levels in the clinical assessment of LN may reflect its severity, while their therapeutic neutralization could be of assistance in its treatment.


This work was supported by local funds from the University of Bari.


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