Elsevier

Immunobiology

Volume 216, Issue 9, September 2011, Pages 1010-1017
Immunobiology

Interaction between oxidative stress and chemokines: Possible pathogenic role in systemic lupus erythematosus and rheumatoid arthritis

https://doi.org/10.1016/j.imbio.2011.04.001Get rights and content

Abstract

Imbalance oxidative stress and chemokines are considered as a universal factors involved in the development of various clinical features seen in the patients with SLE and arthritis. To evaluate the interaction between oxidative stress and chemokines and their relationship with disease activity in SLE and RA patients, oxidative/anti-oxidant profiles and chemokines were assessed. Oxidant and anti-oxidant enzymes were measured in the plasma and the levels of chemokines; MCP-1/CCL2, RANTES/CCL5, MIP-1β/CCL-4 and IP-10/CXCL-10 were evaluated in the serum by an enzyme-linked immunosorbent assay (ELISA). A significant increase in the level of lipid peroxidation was found in SLE and RA patients and positively associated with disease activity. The activities of anti-oxidant enzymes: superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and anti-oxidant molecule GSH were significantly reduced in both diseases. Strong positive associations were found between MDA with RANTES/CCL5 and MIP-1β/CCL4 than MCP-1/CCL-2 in SLE patients while a sturdy connotation was seen with MIP-1β/CCL4 and MCP-1/CCL-2 in RA patients. The anti-oxidant molecule GSH shows a negative association with serum levels of MCP-1/CCL-2, RANTES/CCL5 and IP-10/CXCL-10 in SLE patients and with MCP-1/CCL-2 and RANTES/CCL5 in RA patients. A low level of GSH and high level of RANTES/CCL5 were associated with lupus nephritis patients. These results indicates that excessive production of ROS disturbs redox status and can modulate the expression of inflammatory chemokines leading to inflammatory processes, exacerbating inflammation and affecting tissue damage in autoimmune diseases, as exemplified by their strong association with disease activity.

Introduction

Systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) are two chronic inflammatory and autoimmune disorders of unknown etiology, characterized by diverse autoantibody (Ab) production responses (Amital and Shoenfeld, 2004, Pratt et al., 2009). SLE is accompanied by arthritis/arthralgias, cutaneous rash, vasculitis, neuropsychiatric, renal and cardiopulmonary manifestations (Gordon 2002), whereas the common feature of RA is a predominant synovial proliferation, a destruction of the articular cartilage and activated T-cell infiltration in and around the joints (Goronzy and Weyand 2004). Despite diverse manifestations, the imbalance oxidative stress (Cimen et al., 2000, Taysi et al., 2002) and chemokines (Haringman et al., 2004, Vila et al., 2007) are considered to be the universal factors involved in the development of various clinical features seen in the patients with SLE and arthritis. There has been growing evidence suggesting that infiltration of T lymphocytes and other leucocytes into the sites of inflammation plays a critical role in organ involvement in autoimmune disease (Hoffman 2004). The chemokines are preferentially produced in peripheral tissue at the sites of inflammation and play dual role in inflammation. At these sites they function to recruit neutrophils, monocytes, immature dendritic cells, B cells, and regulation of differential recruitment of T helper (Th1 and Th2) lymphocytes (Baggiolini, 2001, Luster, 1998).

The autoimmune disease like SLE and RA have increased expression of chemokines receptors (CXCR2, CXCR3, CCR3, and CCR1) and elevated levels of chemokines such as MCP-1/CCL2, MIP-1β/CCL-4, SDF-1α/CXCL-12, RANTES/CCL5 and IP-10/CXCL-10 (Klimiuk et al., 2011, Koch et al., 1992, Lit et al., 2006). Recent studies on chemokines showed that it can modulate other functions of the cell such as generation of ROS at the site of inflammation and unregulated by oxidative stimuli (DeForge et al. 1993). These observations added another link to the association between ROS and inflammation, a relationship that, until then, was only viewed as a one-way process, i.e. phagocytes, activated by cytokines or chemotactic factors, produced ROS. The observations also strengthened the concept of ROS as an inflammatory mediator. In addition, these findings often promoted the concept of the glutathione (GSH), the main thiol antioxidant, as an anti-inflammatory mediator. Excessive ROS production disturbs redox status, damages macromolecules, including DNA and can modulate expression of a variety of immune and inflammatory molecules leading to inflammatory processes, exacerbating inflammation and affecting tissue damage (Al Arfaj et al. 2007).

The primary targets of ROS are double bonds in polyunsaturated fatty acids in the cell membrane, which increase lipid peroxidation (LPO) and result in more oxidative damage (Kurien and Scofield, 2006, Perricone et al., 2009). Additionally, oxidative damage mediated by ROS resulting in generation of deleterious by-products, such as aldehydic products, lead to the formation of adducts with proteins that in turn make them highly immunogenic, thus inducing pathogenic antibodies leading to tissue damage in patients with SLE and RA (Kurien and Scofield 2008). Increased lipid peroxidation in serum/plasma and red blood cells (Sarban et al., 2005, Taysi et al., 2002, Turgay et al., 2007) and decreased antioxidant eyzymes; SOD, CAT and Gpx in the patients with SLE (Turgay et al. 2007) and RA (Sarban et al. 2005) confirming the presence of oxidative stress in rheumatoid disease. There are no studies depicting the association of oxidative stress and chemokines in the patients with SLE and RA.

Therefore, the aim of this study was to explore the relationship between oxidative stress and chemokines with the disease activity of rheumatoid disease like SLE and RA, which may have further implications in better understanding of pathology of rheumatoid disease and in the therapeutic management of disease.

Section snippets

Patients and controls

Patients for the study were selected from individuals attending out-patient Department of Internal Medicine at Postgraduate Institute of Medical Education and Research, Chandigarh, India. The study included 30 patients with SLE (26 females and 4 males) with mean age of 26.5 ± 7.48 years, 30 patients with RA (25 females and 5 males) with mean age of 24.2 ± 10.44 and the control group consisted of 30 healthy volunteers (27 females, 3 males) with mean age of 26.73 ± 5.37 years. The patients were

Demographic profile of subjects

The demographic and clinical characteristics of patients with SLE, RA and healthy controls are summarized in Table 1. Most of the patients with SLE and RA had been suffering from the disease for a couple of years. The disease activity in the case of SLE patients was determined by SLE Disease Activity Index (SLEDAI) score (maximum score of 105: Mild score <10; Moderate score 10–20; Severe score >20) showed three patients with moderate SLEDAI score while 27 patients were in the severe score

Discussion

The pathogenesis of autoimmune disease is suggested to be multifactorial and the inflammatory nature of SLE, RA implies that the state of oxidative stress existing in this disease, may contribute to immune-cell dysfunction, autoantigen production and autoantibody reactivity. Increased level of ROS has been implicated in the pathogenesis of SLE and arthritis. Excessive ROS production disturbs redox status, damages macromolecules, including DNA and can modulate expression of a variety of immune

Conflict of interest

The authors indicate no conflicts of interest.

Acknowledgements

The authors are grateful to CSIR, India for financial support. The authors would also like to acknowledge Ashish Aggarwal and Leishangthem Bidyalaxmi Devi for assisting and Dr. Aman Sharma for helping us to analyse the clinical details of the patients. The authors also like to thank all patients and healthy subjects participating in this investigation.

References (47)

  • C. Perricone et al.

    Glutathione: a key player in autoimmunity

    Autoimmun. Rev.

    (2009)
  • A.G. Pratt et al.

    Current concepts in the pathogenesis of early rheumatoid arthritis

    Best Pract. Res. Clin. Rheumatol.

    (2009)
  • S. Sarban et al.

    Plasma total antioxidant capacity, lipid peroxidation, and erythrocyte antioxidant enzyme activities in patients with rheumatoid arthritis and osteoarthritis

    Clin. Biochem.

    (2005)
  • A. Seven et al.

    Lipid, protein, DNA oxidation and antioxidant status in rheumatoid arthritis

    Clin. Biochem.

    (2008)
  • D. Shah et al.

    Oxidative stress in systemic lupus erythematosus: relationship to Th1 cytokine and disease activity

    Immunol. Lett.

    (2010)
  • M. Valko et al.

    Free radicals and antioxidants in normal physiological functions and human disease

    Int. J. Biochem. Cell Biol.

    (2007)
  • A. Zlotnik et al.

    Chemokines: a new classification system and their role in immunity

    Immunity

    (2000)
  • I.M. Allan et al.

    Structural damage to lymphocyte nuclei by H2O2 or gamma irradiation is dependent on the mechanism of OHradical dot radical production

    Br. J. Cancer

    (1988)
  • F.C. Arnett et al.

    The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis

    Arthritis Rheum.

    (1988)
  • M. Baggiolini

    Chemokines in pathology and medicine

    J. Intern. Med.

    (2001)
  • C. Bombardier et al.

    Derivation of the SLEDAI. A disease activity index for lupus patients. The Committee on Prognosis Studies in SLE

    Arthritis Rheum.

    (1992)
  • I.L. Chapple

    Reactive oxygen species and antioxidants in inflammatory diseases

    J. Clin. Periodontol.

    (1997)
  • M.Y. Cimen et al.

    Oxidant/antioxidant status of the erythrocytes from patients with rheumatoid arthritis

    Clin. Rheumatol.

    (2000)
  • Cited by (0)

    View full text