Quercetin and HSC70 coregulate the anti-inflammatory action of the ubiquitin-like protein MNSFß.

BACKGROUND: Quercetin is a flavonol that modifies many cellular processes. Monoclonal nonspecific suppressor factor ß is a member of the ubiquitin-like family of proteins that are involved in various biological processes. It has been demonstrated that quercetin regulates the effect of MNSFß on tumor necrosis factor-α secretion in lipopolysaccharide (LPS)-stimulated macrophages. This study found that quercetin and the heat shock protein HSC70 coregulate the action of MNSFß. METHODS AND RESULTS: Quercetin dose-dependently suppressed the LPS/interferon γ-induced nitric oxide production without cytotoxicity in the macrophage-like cell line Raw264.7. SiRNA knockdown experiments showed that quercetin inhibited the MNSFß and HSC70 siRNA-mediated enhancement of TNFα and the production of RANTES, a member of C-C chemokine superfamily, in LPS-stimulated Raw264.7 cells. Western blot analysis showed that quercetin and HSC70 regulated ERK1/2 activation and LPS-stimulated IκBα degradation by affecting the complex formation of MNSFß and the proapoptotic protein Bcl-G. Moreover, MNSFß is implicated in TLR4/MyD88 signaling but not in TLR3 signaling. CONCLUSIONS: HSC70 is an important chaperone that facilitates the stabilization of MNSFß. Quercetin may negatively control the function of MNSFß by regulating the action of the molecular chaperone HSC70. MNSFß mediates TLR4/Myd88 signaling but not TLR3 signaling.

Stress-induced in vitro apoptosis of native human acute myelogenous leukemia (AML) cells shows a wide variation between patients and is associated with low BCL-2:Bax ratio and low levels of heat shock protein 70 and 90.

Spontaneous in vitro apoptosis reflects a true biological heterogeneity between patients which has to be considered when in vitro models are used to study regulation of apoptosis in native human AML cells. Even though the balance between pro- and anti-apoptotic signaling seems to have a prognostic impact in AML, the possible clinical relevance of spontaneous apoptosis remains to be clarified. High apoptosis/low viability was associated with low levels of heat shock proteins 70 and 90 as well as low Bcl-2:Bax ratio for patients heterogeneous with regard to morphology, membrane molecule expression, genetic abnormalities and response to therapy.