Curcumin modulation of the activation of PYK2 in peripheral blood mononuclear cells from patients with lupus nephritis

Abstract

IntroductionProline-rich tyrosine kinase 2 (PYK2) provides important signals during the activation of lymphocytes, which is essential in autoimmune diseases. Systemic lupus erythematosus (SLE) is a representative autoimmune disease, and lupus nephritis (LN) is one of its most severe complications. Although glucocorticoid-binding immuno-suppression is the first-line therapy for patients with LN, the common and severe side effects of such treatment call for new strategies to improve long-term prognosis and life quality for these patients. Curcumin has been used to treat autoimmune disease with good curative effect, but little is known about the effect of curcumin on LN patients. Our aim was to investigate the mechanism of curcumin for management of LN, specifically regarding the PYK2 pathways.Material and methodsFreshly isolated peripheral blood mononuclear cells (PBMCs) from 20 LN patients and 20 healthy individuals were cultured and stimulated with either PMA, PMA+TyrA9 (PYK2 specific inhibitor), or PMA+Curcumin, and with PBS as control. After 48 hours of incubation, cells were harvested and the expression of PYK2, p-PYK2, CD40L, CTLA-4, and PBMCs proliferation were measured. Then the expression and activation of PYK2 was evaluated using Western blot, the expression of costimulatory molecules CD40L and CTLA-4 protein was evaluated using flow cytometry, and PBMC proliferation was assessed using a [3H]-thymidine incorporation assay.ResultsCurcumin inhibited the expression and activation of PYK2 in PBMCs in patients with LN in vitro. The inhibition rate of curcumin was negatively correlated with the level of serum complement, but positively correlated with 24-h proteinuria. Curcumin also suppressed the expression of costimulatory molecules CD40L and CTLA-4, as well as PBMC proliferation. Interestingly, these effects were not reproduced on PBMC cultures of healthy subjects.ConclusionsThe inhibition of PYK2 signalling protein may be one of the mechanisms underlying the action of curcumin in LN treatment.

Immunomodulatory Effects of Diet and Nutrients in Systemic Lupus Erythematosus (SLE): A Systematic Review

“…Contrary to this, another study revealed that administration of low doses of curcumin (0.1 and 1.0 µg/mL) to cultured CD4 + cells from patients with SLE significantly (p < 0.001) modulated the Th17/Treg balance without affecting healthy subjects (187). Similar to this in vitro experiment, low-dose curcumin (0.1 µg/mL) inhibited the expression and activation of PYK2 in peripheral blood mononuclear cells (PBMCs) and reduced the proliferation of PBMCs in patients with lupus nephritis (188).…”

The impact of curcumin supplementation on systemic lupus erythematosus and lupus nephritis: A systematic review

“…15 This PYK2 reduction was accompanied by an associated decrease in 24hr proteinuria (p < 0.01). 15 Serological markers. The same group, Wang et al, showed that complement C3 levels were negatively correlated with curcumin inhibition.…”

Immunomodulatory effects of curcumin in systemic autoimmune diseases

“…In vitro studies have also revealed that curcumin decreases total IgG, serum levels of BAFF following toll‐like receptor (TLR) 4 stimulation, B‐cell activation in MRL/lpr mice, and reduces lupus nephritis in MRL/lpr mice, which may represent an overall therapeutic strategy in the management of SLE (Abrahams et al, 2019). Moreover, curcumin inhibited the upregulation and stimulation of proline‐rich tyrosine kinase 2(PYK2) in vitro in PBMCs obtained from patients with lupus nephritis (M. Wang et al, 2017). PYK2 is a nonreceptor protein tyrosine kinase that is essentially connected to focal adhesion kinase (FAK) and implicated in blocking costimulatory molecules (including CD40L and CTLA‐4) and cell growth (Cong, Wang, Konrad, Schoeb, & Elson, 2009).…”

“…In vitro studies have also revealed that curcumin decreases total IgG, serum levels of BAFF following toll-like receptor (TLR) 4 stimulation, B-cell activation in MRL/lpr mice, and reduces lupus nephritis in MRL/lpr mice, which may represent an overall therapeutic strategy in the management of SLE(Abrahams et al, 2019). Moreover, curcumin inhibited the upregulation and stimulation of proline-rich tyrosine kinase 2(PYK2) in vitro in PBMCs obtained from patients with lupus nephritis (M Wang et al, 2017)…”