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Baicalein is one of the bioactive compounds extracted from Scutellaria baicalensis. Recent studies indicated the antitumor effects of baicalein, however, the underlying mechanisms are needed to be further determined. In this study, we found that baicalein could inhibit the tumor growth in mice models of breast cancer and melanoma and worked as an immunomodulator to promote the infiltration of tumor-associated macrophages (TAMs) and skew the TAMs towards the M1-like phenotype. Baicalein also induced M1-like phenotype polarization in THP-1-derived macrophages. Meanwhile, the expression of pro-inflammatory factors associated with M1 macrophages, including TNF-α, IL-1β, CXCL9 and CXCL10, were increased after baicalein treatment. Mechanistically, the RNA-seq data suggested that baicalein potentiated the M1 macrophage polarization via the NF-κB/TNF-α signaling pathway. ELISA and confocal microscopy assay confirmed that baicalein significantly induced the production of TNF-α and the activation of NF-κB, while TNF-α neutralization inhibited baicalein-induced macrophage polarization toward M1, and NF-κB P65 knock-down suppressed baicalein-induced TNF-α production in THP-1-derived macrophages. Phosphoinositide 3-kinase (PI3k) γ has been reported as a key molecule in macrophage polarization, and inhibition of PI3Kγ activates the NF-κB-related inflammatory signals. Our pharmacological network analysis predicted that PI3Kγ might be one of the major targets of baicalein. The results from the docking program and surface plasmon resonance (SPR) confirmed that baicalein displayed good binding activity to PI3Kγ. We further found that baicalein not only exhibited a direct inhibitory effect on the protein kinase activity of PI3Kγ, but also reduced the mRNA and protein expression of PI3Kγ, indicating that baicalein might be a novel PI3Kγ inhibitor. In summary, baicalein mediated the TAMs skewing to M1-TAMs, and then retarded tumor growth. These effects, at least in part, were linked to the PI3Kγ/NF-κB signaling.

Objective: To study the expression and clinical significance of NF-kB, CTGF and OPN in mononuclear cells in peripheral blood as well as renal tissues in patients with IgA nephropathy. Methods: A total of 25 nephropathy patients diagnosed with IgA nephropathy and 25 patients receiving nephrectomy due to trauma or tumor in our hospital were studied. Peripheral blood and kidney tissues were collected to test NF-kB, CTGF, OPN, T-bet, GATA-3, RORγT and Foxp3 expressions. Results: CTGF and OPN percentages in peripheral blood mononuclear cells and kidney tissues of nephropathy patients were higher than those of the control group. NF-kB, CTGF and OPN expressions were significantly higher in M1, E1, S1 group patients’ peripheral blood mononuclear cells and renal tissues than those in M0, E1 and S1 group. T-bet, GATA-3 and RORγT expressions in nephropathy patients’ peripheral blood were significantly higher than those in the control group, and were positively correlated with NF-kB, CTGF and OPN expressions. The expression of Foxp3 was significantly lower than that of control group, and was negatively correlated with NF-kB, CTGF and OPN expressions. Conclusions: The expression of NF-kB, CTGF and OPN in peripheral blood mononuclear cells and renal tissue in patients with IgA nephropathy is abnormally high and can evaluate the prognosis of the disease and the differentiation of CD4+T cells.

The BAFF-receptor (BAFFR) is encoded by the TNFRSF13C gene and is one of the main pro-survival receptors in B cells. Its function is impressively documented in humans by a homozygous deletion within exon 2, which leads to an almost complete block of B cell development at the stage of immature/transitional B cells. The resulting immunodeficiency is characterized by B-lymphopenia, agammaglobulinemia, and impaired humoral immune responses. However, different from mutations affecting pathway components coupled to B cell antigen receptor (BCR) signaling, BAFFR-deficient B cells can still develop into IgA-secreting plasma cells. Therefore, BAFFR deficiency in humans is characterized by very few circulating B cells, very low IgM and IgG serum concentrations but normal or high IgA levels.

International audience; Piracy of the NF-kB transcription factors signaling pathway, to sustain its activity, is a mechanism often deployed in B-cell lymphoma to promote unlimited growth and survival. The aggressive activated B-cell like (ABC) subtype of diffuse large B-cell lymphoma (DLBCL) exploits a multi-protein complex of CARMA1, BCL10 and MALT1 (CBM complex), which normally conveys NF-kB signaling upon antigen receptors engagement. Once assembled, the CBM also unleashes MALT1 protease activity to finely tune the immune response. As a result, ABC DLBCL tumors develop a profound addiction to NF-kB and to MALT1 enzyme, leaving open a breach for therapeutics. However, the pleiotropic nature of NF-kB jeopardizes the success of its targeting and urges us to develop new strategies. In this review, we discuss how post-translational modifications, such as phosphorylation and ubiquitination of the CBM components, as well as, MALT1 proteolytic activity, shape the CBM activity in lymphocytes and ABC DLBCL, and may provide new avenues to restore vulnerability in lymphoma.

All-trans retinoic acid(ATRA)は核内受容体であるretinoic acid receptor(RAR)のリガンドであり,消化管を含む多くの組織で重要な生理作用を有している.最近,臨床的なレチノイン酸の使用と炎症性腸疾患との関連が注目されているが,この問題に関する基礎的な検討は行われていない.今回我々は,大腸癌由来細胞株を用いて,炎症・免疫応答において中心的な役割を果たしているnuclear factor- k B(NF-k B)シグナリングに対するATRA の影響について,レポーター遺伝子解析法,リアルタイム定量的 RT-PCR法にて検討を行った.ATRA および他のレチノイド化合物(9-cis retinoic acid,13-cis retinoic acid,AM580,retinol)は,大腸癌由来細胞株において用量依存性に NF-k B を活性化した.また,ATRA はNF-k B の代表的な標的遺伝子であるIL-8の発現を誘導した.RAR の活性化と比較するとNF-k B 活性化に要するATRA の濃度域は高かった.TNF-a によるNF-k B の活性化,IL-8発現誘導は,ATRA をプレインキュベーションすることにより著明に増大し,相乗的な効果が認められた.ATRA はNF-k B サブユニット(RelA,p50)の発現を増大させ,TNF受容体(TNFR1)の発現レベルも上昇させていた.これらの結果より,レチノイン酸は大腸上皮細胞においてNF-k B シグナリングを活性化し,TNF-a に対する感受性を増大させている可能性が示唆された., All-trans retinoic acid(ATRA)is a ligand for the retinoicacid receptor(RAR), a member of the nuclear receptorsuperfamily, and it is well established that RARs play acritical role in the development and differentiation of variousorgans including gastrointestinal tract. Recently, severalcase reports suggested a possible association between theclinical use of retinoic acid and inflammatory bowel diseases.However, it is not known whether ATRA affects the inflammatoryresponse of colonic epithelial cells. In this study,we examined the effect of ATRA on NF-k B activity andIL-8 expression in colonic epithelial cells in vitro. NF-k Bactivation and RAR activation were assessed by the reportergene assay and IL-8 mRNA expression was assessed bythe real-time quantitative RT-PCR. ATRA and other retinoidcompounds(9-cis retinoic acid, 13-cis retinoic acid,AM580 and retinol)activated NF-k B in a dose- and timedependentmanner in colonic cell lines(HCT116, Caco2,SW480, DLD-1, and LS174T). However, compared to RARactivation, much higher concentrations of ATRA wereneeded to activate NF-k B. ATRA also up-regulated theexpression of IL-8, a target gene of NF-k B. ATRA-inducedNF-k B activation was repressed by a MEK inhibitorand a p38 MAP kinase inhibitor. Preincubation with ATRAsignificantly potentiated TNF-a -induced activation of NFkB and TNF-a -induced expression of IL-8. ATRA wasfound to up-regulate the expression of NF-k B subunits(RelA and p50)and TNF-a receptor 1. These results suggestthat ATRA and other retinoid compounds can activateNF-k B signaling and potentiate the inflammatory responseto TNF-a in colonic epithelial cells.

Cancer cells may often support their own growth, survival, and drug resistance by autocrine/paracrine loops based on the production of different factors; results from us and others have shown that similar interleukin-6 (IL-6)-related loops are operative in multiple myeloma and prostate or renal cancer. Because this aspect has not been investigated in detail for hepatocellular carcinoma (HCC), we have examined it in HA22T/VGH cells. These differ from other primary liver cancer cell lines (that is, HepG2, HuH-6, and HuH-7) in that enzyme-linked immunosorbent assay (ELISA) showed the HA22T/VGH cells to secrete remarkable amounts of IL-6 (16.8 ng/10(6) cells/24 h); this production, due to constitutive activation of NF-kappa B, is inhibited by agents like curcumin and dehydroxymethylepoxyquinomicin (DHMEQ), which interfere with the transcription factor. Flow cytometry, ELISA, mRNA, and Western blotting analyses were performed to characterize the status of the IL-6 receptor in HA22T/VGH cells. Two transmembrane glycoproteins that form the functional IL-6 receptor have been identified: the ligand-binding gp80 and the signal-transducer gp130. Soluble forms of gp80 also trigger membrane gp130 signaling when complexed with IL-6, while soluble forms of gp130 inhibit the same process. Our results showed that HA22T/VGH cells express gp130 at their surface, but release only traces of its soluble form. For gp80, the cells produced the mRNAs of both its membrane and soluble form. However, in immunoblotting they exhibited a very faint content of the same subunit, which, in addition, was neither expressed at the cell surface nor secreted. In MTT assays, incubation with a neutralizing anti-IL-6 antibody for up to 7 days did not affect the growth of HA22T/VGH cells. Also, other specific anti-IL-6 approaches (siRNA or AODN) failed to produce this result. In conclusion, autostimulatory loops mediated by IL-6 are less likely to occur in HCC than in other kinds of cancer. However, since release of IL-6 is frequent in HCC, especially in its more advanced stages, the use of agents like curcumin or DHMEQ might be beneficial to counteract its adverse systemic effects (e.g., cachexia).