The epidermal growth factor receptor (EGFR) has a close relation to lung cancer; its role in the pathogenesis of lung cancer is to be further elucidated. The results of this study indicate that about 80% exosomes purified from the LC biopsies contained EGFR; only about 2% exosomes contained EGFR in the samples from chronic lung inflammation. The purified exosomes induced tolerogenic DCs. Coculture of the tolerogenic DCs and Th0 cells generated the tumor antigen-specific regulatory T cells (Treg). The Tregs could suppress the tumor antigen specific CD8+ T cells.

Macrophage polarization is implicated in the inflammation in obesity. The aim of the present study was to examine the anti-inflammatory activities of botanical triterpene celastrol against diet-induced obesity. We treated diet-induced obese C57BL/6N male mice with celastrol (5, 7.5 mg/kg/d) for 3 weeks, and investigated macrophage M1/M2 polarization in adipose and hepatic tissues. Celastrol reduced fat accumulation and ameliorated glucose tolerance and insulin sensitivity. Celastrol down-regulated the mRNA levels of macrophage M1 biomarkers (e.g., IL-6, IL-1β, TNF-α, iNOS) in cell culture and in mice. The underlying mechanisms were investigated in murine macrophage RAW264.7 cells. Our results demonstrated that celastrol might control macrophage polarization through modulating the cross-talk between the following three mechanisms: 1) suppressing LPS-induced activation of MAP kinases (e.g., ERK1/2, p38, JNK) in a concentration dependent manner; 2) attenuating LPS-induced nuclear translocation of NF-κB p65 subunit in a time dependent manner; 3) activating Nrf2 and subsequently inducing HO-1 expression. HO-1 inhibitor SnPP diminished the inhibitory effects of celastrol on the activation of NF-κB pathway and the pro-inflammatory M1 macrophage polarization. Taken together, celastrol exhibited anti-obesity effects via suppressing pro-inflammatory M1 macrophage polarization. Thus, our results provide new evidence for the potential of celastrol in the treatment of obesity.

The interaction of heparan sulfate with different ligand proteins depends on the precise location of O-sulfate groups in the polysaccharide chain. We have previously shown that overexpression in human kidney 293 cells of a mouse mastocytoma 2-O-sulfotransferase (2-OST), previously thought to catalyze the transfer of sulfate from 3'-phosphoadenosine 5'-phosphosulfate to C2 of L-iduronyl residues, preferentially increases the level of 2-O-sulfation of D-glucuronyl units [Rong, J., Habuchi, H., Kimata, K., Lindahl, U., and Kusche-Gullberg, M. (2000) Biochem. J. 346, 463-468]. In the study presented here, we further investigated the substrate specificity of the mouse mastocytoma 2-OST. Different polysaccharide acceptor substrates were incubated with cell extracts from 2-OST-transfected 293 cells together with the sulfate donor 3'-phosphoadenosine 5'-phospho[(35)S]sulfate. Incubations with O-desulfated heparin, predominantly composed of [(4)alphaIdoA(1)-(4)alphaGlcNSO(3)(1)-](n)(), resulted in 2-O-sulfation of iduronic acid. When, on the other hand, an N-sulfated capsular polysaccharide from Escherichia coli K5, with the structure [(4)betaGlcA(1)-(4)alphaGlcNSO(3)(1)-](n)(), was used as an acceptor, sulfate was transferred almost exclusively to C2 of glucuronic acid. Substrates containing both iduronic and glucuronic acid residues in about equal proportions strongly favored sulfation of iduronic acid. In agreement with these results, the 2-OST was found to have a approximately 5-fold higher affinity for iduronic acid-containing substrate disaccharide units (K(m) approximately 3.7 microM) than for glucuronic acid-containing substrate disaccharide units (K(m) approximately 19.3 microM).

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