Possible involvement of IL-18 in SLE-dysregulated apoptosis and cytopenia

Abstract

Background and objectives: Tissue homeostasis is maintained through a balance between cell proliferation and apoptotic cell death. Dysregulated apoptosis leads to development of autoimmunity like systemic lupus erythematosus (SLE). One of the key biological responses induced by IL-18 is that in combination with IL-12 it stimulates Th1 cell differentiation and involvement in immune responses. Up regulation of Fas ligand in Th1 cells by IL-18 may increase apoptosis of Fas receptor expressing cells that interact with activated Th1 cells. This induction of apoptosis may allow IL-18 to play a role in chronic inflammatory and autoimmune conditions. The aim of this study is to quantify the percentage of apoptotic peripheral blood neutrophils in SLE and to determine the relation with cytopenia. Also the serum level of the proinflammatory cytokine IL-18 is measured in SLE to be correlated with apoptotic neutrophils and other studied parameters. Methods: Neutrophil apoptosis in 30 SLE patients and 15 healthy controls was assessed by flow cytometry using annexin V and 7AAD binding. Serum IL-18 was measured by ELISA and CBC was done by automated cell counter. Results: The percentage of total, early and late apoptotic neutrophils, determined by annexin V and 7AAD binding, was increased in peripheral blood of SLE patients without corticosteroid therapy (group I, n=15) (54.2 ± 16.3 %, 36.35 ± 13.9 % and 17.8 ± 6.4 % respectively) and also SLE patients with corticosteroid therapy (group II, n=15) (47.3 ± 28.1 %, 37.1 ± 25.6 % and 10.1 ± 6.6 % respectively) compared with normal controls (group III, n=15) (7.24 ± 3.7 %, 2.5 ± 1.5 % and 4.7 ± 2.9 % respectively). SLE neutrophil apoptosis correlated negatively with WBC (p=0.01) in group I. Serum IL-18 was significantly elevated in SLE patients with renal complication within group I when compared with SLE patients without renal complication within the same group (p=0.01) and correlated positively with SLE disease activity index (SLEDAI) (p=0.001). In group II; IL-18 revealed significant negative correlation with % of both total and early apoptotic neutrophils (p=0.02) and highly significant negative correlation with absolute lymphocytes (p<0.0001). Conclusion: Increased circulating apoptotic neutrophils in SLE patients may be a pattern of unbalanced process of both apoptosis and clearance of apoptotic material. Neutrophil apoptosis may be a significant cause for SLE associated cytopenia. Effect of IL-18 on neutrophil apoptosis and clearance may be masked or opposed by other undetermined factors in SLE. Corticosteroid therapy may improve neutrophil apoptotic clearance as well as IL-18 inflammatory and antiapoptotic effects in SLE.