Up-regulation of IL-18 and predominance of a Th1 immune response is a hallmark of lupus nephritis

Abstract

SUMMARYThere is evidence that nephritis is dominated by a Th1 immune response in systemic lupus erythematosus. Since IL-18 promotes polarization of the immune response toward Th1, we investigated the role of this cytokine in lupus nephritis (LN). A total of 133 lupus patients and 44 healthy subjects were enrolled. Demographic and clinical characteristics with renal biopsy data were recorded. IL-18 along with IFN-g and IL-4, two prototypical of Th1 and Th2 cytokines, were measured in serum by ELISA. Peripheral blood lymphocytes were analysed by flow cytometry for IFN-g and IL-4. IL-18 expression was determined by immunohistochemistry in 13 renal biopsy specimens from patients with LN and 2 controls. Serum IL-18 was higher in lupus patients than in controls. Levels of IL-18 correlated with urinary microalbumin and were increased in patients with LN when compared to those without LN. IL-18 expression was also increased within the glomeruli of nephritic patients and was primarily detected within the mesangial matrix and in infiltrating mononuclear cells. Measurement of IFN-g and IL-4 in either sera or peripheral blood lymphocytes showed high IFN-g along with low IL-4 expression in LN patients compared to patients without nephritis. A positive correlation between serum IL-18 and IFNg levels was found. IL-18 may play a prominent role in the pathogenesis of LN by promoting a cytokine imbalance towards a Th1 immune response. Measurement of IL-18 may be helpful for the early identification of lupus patients with LN and may help gauge the response to treatment in patients with active LN undergoing treatment.

Th17 and natural Treg cell population dynamics in systemic lupus erythematosus

“…Previous findings supported the notion that Th1 cytokines could play an important role in inflammation and tissue injury and are correlated with the development of SLE and, in particular, lupus glomerulonephritis (43)(44)(45)(46). We detected IL-17ϩ T cells in MRL/lpr mouse kidneys (data not shown), but whether Th17 cells are implicated in these forms of SLE requires further investigation.…”

Aberrant Phenotype and Function of Myeloid Dendritic Cells in Systemic Lupus Erythematosus

“…Other alterations include changes in proliferative T cell responses as well as increased expression of early and late T cell activation markers (3, 7, 9 -11). In addition, alterations in Th1 and/or Th2 lymphocyte function have been described (12)(13)(14)(15)(16), resulting in production of cytokines that up-regulate autoantibody production by B cells, promote immune complex formation, and increase the apoptotic load (17,18). The exact role that accessory cells might have in inducing abnormal T cell responses in SLE is unclear; however, different groups have proposed that T cell disturbances in SLE could be induced or promoted, at least in part, by alterations in dendritic cell (DC) phenotype and function, because these are key regulators of the immune system (19 -22).…”

Disease association of the interleukin-18 promoter polymorphisms in Taiwan Chinese systemic lupus erythematosus patients

“…16,38 In addition, SLE patients have significant higher serum concentrations of IL-18. 16 From the SLE development, the deficiency in enhanced gene transcription will be beneficial for the individual, as elevated levels of the proinflammatory IL-18 protein mediate many of the acute and chronic inflammatory processes. Indeed, studies in anticytokine therapy including TNF, IL-6, IL-18 and IFN-g in SLE have become an important issue in preventing from tissue damage.…”

“…A previous report showed that haplotype-TAC at position À656, À607 and À137, respectively, would lead to low promoter activity compared with other haplotypes-GCG and TAG.23 This may answer why the ht2 (TAC) haplotype is less in SLE patients than in controls because elevated serum IL-18 of SLE patients are observed as compared with normal individuals. [11][12][13]16 However, no further information about ht4 (GAC) haplotype in promoter activity assay is available. We cannot exclude other polymorphism-like position at À656 which may also contribute to the transcriptional activity of IL-18.…”

“…[10][11][12][13][14][15] Among these cytokines, elevated serum IL-18 of SLE patients are observed as compared with normal individuals. [11][12][13]16 IL-18, a member of the IL-1 cytokine family, is a proinflammatory cytokine. This cytokine is now recognized as an important regulator of innate and acquired immune responses and plays multiple roles in chronic inflammation, in autoimmune diseases, in a variety of cancers and in number of infectious diseases.…”