984 - Upregulated High Mobility Group Box One Acts in Synergy with Danger Signals Through the Activation of of p38 Mitogen-Activated Protein Kinases to Promote Inflammation in Patients with Lupus Nephritis

Monday, November 7, 2011: 9:00 AM-6:00 PM
Hall F2 - Poster Hall (McCormick Place West)
Shui-Lian Yu, Chun-Kwok Wong, Da-Peng Chen, cheuk-Chun Szeto, Edmund K. Li and Lai-Shan Tam, The Chinese University of Hong Kong, Hong Kong, China
Presentation Number: 984

Background/Purpose: The chromatin DNA binding protein high mobility group box one (HMGB1) has previously been demonstrated to act as an “alarm” prototypical damage associated molecular pattern (DAMP) to contribute to the pathogenesis of SLE via breaking the immunological tolerance against nucleosomes/dsDNA, yet its mode of action is still not well defined. To assess the balance between the levels of receptor for advanced glycation end products (RAGE), RAGE ligand (HMGB1) and soluble RAGE in active lupus patients (systemic lupus erythematosus disease activity index, SLEDAI > 4), and subsequently explore the modulating and synergy effects of HMGB1 with endogenous and exogenous danger signals on its downstream cytokine in lupus patients. 

 Method: Plasma HMGB1 and soluble RAGE were detected in lupus patients and healthy controls (HCs) by enzyme-linked immunosorbent assay. Monocyte cell surface RAGE expression was assessed using flow cytometry. Ex vivo production of inflammatory cytokines (IL-1β, IL-6, IL-8, IL-10, TNF-α and IL-12p70) from monocytes of lupus patients and HCs upon 24 hours HMGB1 stimulation was assessed using human inflammatory cytokine Cytometric Bead Array with flow cytometry.

Result: Elevated plasma levels of HMGB1 in lupus patients were positively correlated with SLEDAI (both p < 0.05). Significantly lower concentrations of soluble RAGE were found in lupus plasma, albeit higher protein expression on monocytes than HCs. Recombinant HMGB1 (rHMGB1) could significantly induce the ex vivo production of IL-6 from monocytes of lupus patients. Moreover, there was an observable elevated release of proinflammatory (IL-6 and IL-12p70) from monocyte in lupus patients upon the stimulation with TLR9 ligand (CpG-ODNs) or nuclear extract alone than that of HCs. Strong enhancing effects on induction of IL-6 and IL-12p70 occurred when HMGB1 in combination with CpG-ODNs, which subsequently promoted the phosphorylation of p38 mitogen-activated protein kinases (MAPK) in monocytes.

Conclusion: Upregulated alarmin HMGB1 may act in synergy with TLR9 ligand (CpG-ODNs) through the activation of p38 MAPK to promote the production of proinflammatory (IL-6 and IL-12) in monocytes of patients with Lupus Nephritis.

Keywords: inflammation and lupus nephritis

Disclosure: S. L. Yu, None; C. K. Wong, None; D. P. Chen, None; C. C. Szeto, None; E. K. Li, None; L. S. Tam, None.