Brusatol Derivative–34 Attenuates Allergic Airway Inflammation Via Inhibition of the Spleen Tyrosine Kinase Pathway

Brusatol derivative-34 (Bru-34), a derivative of brusatol, has been shown significantly anti-inflammatory activity in mice in our previously work. However, to our knowledge, there were very limited studies on how Bru-34 affected airway inflammation. Thus, in this present study, the effects and potential mechanisms of Bru-34 on allergic airway inflammation were examined both in vivo and in vitro. The results showed that Bru-34 attenuated the allergic airway inflammation in mice, with significant decreasing of the inflammatory cells and mediators in bronchoalveolar lavage fluids and attenuation of the histopathological alterations in the lung tissues. In addition, Bru-34 significantly inhibited the release of inflammatory cytokines in antigen induced rat basophilic leukemia -2H3 (RBL-2H3) cells. What’s more, Bru-34 significantly decreased the expression of spleen tyrosine kinase (Syk), p-Syk, cytoplasmic phospholipase A2 (cPLA2), p-cPLA2, nuclear factor-κB (NF-κB) and p-NF-κB both in allergic mice lung tissue and antigen induced RBL-2H3 cells. Furthermore, the collaborative effects of Bru-34 with inhibitors against Syk, cPLA2, and NF-κB, showed that Syk was an important target of Bru-34, and cPLA2 and NF-κB played important roles in the coordinated inflammatory response. In conclusion, Bru-34 could significantly modulate the allergic airway inflammation, and its potential mechanism was revealed at least partially via down-regulating of Syk-cPLA2 -NF-κB signaling.

Spleen Tyrosine Kinase Inhibition Ameliorates Tubular Inflammation in IgA Nephropathy

Spleen tyrosine kinase (Syk) is a non-receptor tyrosine kinase involved in signal transduction in a variety of immune responses. It has been demonstrated that Syk plays a pathogenic role in orchestrating inflammatory responses and cell proliferation in human mesangial cells (HMC) in IgA nephropathy (IgAN). However, whether Syk is involved in tubular damage in IgAN remains unknown. Using human kidney biopsy specimens, we found that Syk was activated in renal tubules of biopsy-proven IgAN patients with an increase in total and phosphorylated levels compared to that from healthy control subjects. In vitro, cultured proximal tubular epithelial cells (PTECs) were stimulated with conditioned medium prepared from human mesangial cells incubated with polymeric IgA (IgA-HMC) from patients with IgAN or healthy control. Induction of IL-6, IL-8, and ICAM-1 synthesis from cultured PTECs incubated with IgA-HMC conditioned medium was significantly suppressed by treatment with the Syk inhibitor R406 compared to that from healthy control. Furthermore, R406 downregulated expression of phosphorylated p65 NF-κB and p-42/p-44 MAPK, and attenuated TNF-α-induced cytokine production in PTECs. Taken together, our findings suggest that Syk mediates IgA-HMC conditioned medium-induced inflammation in tubular cells via activation of NF-κB and p-42/p-44 MAPK signaling. Inhibition of Syk may be a potential therapeutic approach for tubulointerstitial injury in IgAN.