Introduction
Systemic lupus erythematosus (SLE) is a devastating, chronic and inflammatory autoimmune disorder that can virtually affect any organ in the body. SLE occurs 10 times more commonly in women than men, and autoantibodies are a cardinal feature of the disease, occurring up to 10 years prior to disease diagnosis.1–5
Sjögren's syndrome (SS) shares some of the features of SLE, being a debilitating systemic and chronic inflammatory, autoimmune disorder characterised by autoantibodies. The main features of SS are diminished lacrimal/salivary gland secretion (sicca complex), resulting in keratoconjunctivitis sicca and xerostomia.6–8
MRL-lpr/lpr mice as an animal model of SLE/SS
MRL-lpr/lpr mice resemble human SLE in several ways, and therefore, is a widely used animal model.9–18 MRL-lpr/lpr mouse has a single-gene mutation (lpr) of the fas apoptosis gene on mouse chromosome 19, and therefore, a defect in apoptotic death of lymphocytes. There is massive accumulation of CD4−CD8− T lymphocytes and development of a disease similar to human SLE. Even though lymphoproliferation in human lupus is not as prominent in majority, other features like lupus nephritis, skin lesions, arthritis and neurological manifestations match well. However, lymphadenopathy with double-negative T-cell proliferation may mimic the defective apoptotic mechanisms and its clearance in human lupus.
MRL-lpr/lpr mice develop salivary and lacrimal gland lymphocytic infiltrates similar to human SS, but without functional loss.13–15
MRL-MPJ mice
MRL/MpJ mice, even though they have the normal Fas gene, develop autoimmune symptoms much later than the MRL-lpr/lpr mice. MRL/MpJ inbred female mice have a lifespan of 73 weeks, while males live for 93 weeks. MRL-lpr/lpr female mice typically die at 17 weeks of age while the males die at 22 weeks. MRL-MpJ mice serve as a control for the MRL-lpr/lpr mice (http://jaxmice.jax.org/strain/000486.html).
The aetiology of SLE/SS is largely unknown. There is no effective treatment for SLE/SS, other than immunosuppressives. Current treatment modalities are fraught with significant side effects. Therefore, it is paramount to have studies that can identify new therapeutic agents with few side effects.
Ultrasoluble curcumin
Our studies showing significantly increased oxidative damage in lupus patients19–21 led us to investigate an antioxidant/anti-inflammatory agent known as curcumin,22–31 obtained from the rhizome of Curcuma longa (turmeric). Curcumin (1,7-bis[4-hydroxy-3-methoxyphenyl]-1,6-heptadiene-3,5-dione), a naturally occurring ‘nutraceutical’, comprises 4–6% of turmeric.
Commercial curcumin contains curcumin compound (77%), demethoxycurcumin (DMC) (17%) and bisdemethoxycurcumin (BDMC) (3%). Curcumin, when abbreviated CU, will refer to the commercially available mixture containing all three curcuminoid compounds.
CU has been studied in prostate, oesophagus, lung, breast and oral cancers.32–35 Recently, CU was shown to suppress nuclear factor-kB and increase apoptosis in both Flo-1 and OE33 oesophageal adenocarcinoma cell lines36 ,37 CU also induces release of cytochrome C, activation of caspases and p53 and brings about antiangiogenic effects through downregulation of vascular endothelial growth factor.38 ,39 TU oil has been shown to have antifungal, mosquitocidal, insecticidal, antibacterial, antioxidant, antimutagenic and anticancer activities.40–43
Most in vitro or in vivo studies are carried out with CU dissolved in organic solvents or as CU powder mixed in animal feed. We have shown that heat treatment (100°C) increased CU/TU solubility 12-fold/3-fold, respectively, in water.44 Subsequently, we found that heat/pressure (121°C/15 psi) treatment increased CU solubility 35-fold (ultrasoluble CU (UsC); unpublished data). Our antibody-antigen inhibition studies with CU45 suggested a possible route of therapeutic intervention for experimental SLE and SS. To test this, we administered water, UsC or ultrasoluble turmeric (UsT) to six MRL-lpr/lpr or MpJ mice each.