Tubular NF-κB is overexpressed in proteinuric patients with IgA nephropathy

Increasing evidence suggests that nuclear factor κB (NF-κB) plays a pivotal role in many glomerulopathies. Therefore, the aim of the present study was to determine the tubular immunoexpression of NF-κB in non-proteinuric (n = 22) and proteinuric patients (n = 16) with IgA nephropathy (IgAN). Another purpose of this study was to examine the possible relationship between NF-κB immunoexpression and proteinuria, interstitial fibrosis as well as interstitial infiltrates. Tubular immunoexpression of NF-κB, interstitial monocytes/macrophages, T lymphocytes, B lymphocytes and interstitial area were determined using a computer image analysis system. The mean values of the tubular immunoexpression of NF-κB, interstitial area and interstitial monocytes/macrophages were in proteinuric IgAN patients significantly increased compared to non-proteinuric IgAN cases, whereas interstitial T and B lymphocytes did not differ between these groups. In proteinuric patients, tubular immunoexpression of NF-κB was highly significantly positively correlated with the degree of proteinuria. Moreover, in both the non-proteinuric and the proteinuric groups with IgAN, tubular immunoexpression of NF-κB was positively correlated with the interstitial area and interstitial monocytes/macrophages. Our findings raise the possibility that proteinuria causes tubular overexpression of NF-κB and, in the process, recruitment of monocytes/macrophages and tubulointerstitial injury in IgAN patients.     

Functional characterization of the NF-κB transcription factor gene REL2 from Anopheles gambiae

The REL2 gene plays an important role in innate immunity against both Gram （＋） and Gram （-） bacteria and malaria parasites in Anopheles gambiae, the main vector of malaria in Africa. Through alternative splicing, REL2 produces two protein products, REL2F （with a Rel-homology domain as well as an inhibitory ankyrin repeat region） and REL2S （without the ankyrin repeats）. In the immune-competent cell line SualB from An. gambiae, REL2 has been shown to be a key regulator for cecropin A （or CEC1）. The high level expression of CEC1 in SualB was postulated to be the result of constitutive activation of REL2F. Here we showed that REL2F is indeed processed, albeit at a low level, in the SualB cell line. The primary cleavage requires residue 678 （an aspartic acid）. Proteolytic cleavage of REL2F can be enhanced by challenge with bacteria Escherichia coli and Bacillus subtilis, but not with fungus Beauveria bassiana. The inducible cleavage can be substantially reduced by RNA interference against PGRP-LC and CASPL1. Over-expression of REL2S or a constitutively active form of REL2F （REL2F380C or REL2F678） in An. gambiae cell line can further increase expression of CEC1 and other antimicrobial peptide genes. Over-expression of these constitutive active proteins in an immune naive cell line, MSQ43, from Anopheles stephensi, results in even more dramatic increased expression of antimicrobial peptides.     

Pirh2 mediates the sensitivity of myeloma cells to bortezomib via canonical NF-κB signaling pathway

Clinical success of the proteasome inhibitor established bortezomib as one of the most effective drugs in treatment of multiple myeloma (MM). While survival benefit of bortezomib generated new treatment strategies, the primary and secondary resistance of MM cells to bortezomib remains a clinical concern. This study aimed to highlight the role of p53-induced RING-H2 (Pirh2) in the acquisition of bortezomib resistance in MM and to clarify the function and mechanism of action of Pirh2 in MM cell growth and resistance, thereby providing the basis for new therapeutic targets for MM. The proteasome inhibitor bortezomib has been established as one of the most effective drugs for treating MM. We demonstrated that bortezomib resistance in MM cells resulted from a reduction in Pirh2 protein levels. Pirh2 overexpression overcame bortezomib resistance and restored the sensitivity of myeloma cells to bortezomib, while a reduction in Pirh2 levels was correlated with bortezomib resistance. The levels of nuclear factorkappaB (NF-κB) p65, pp65, pIKBa, and IKKa were higher in bortezomib-resistant cells than those in parental cells. Pirh2 overexpression reduced the levels of pIKBa and IKKa, while the knockdown of Pirh2 via short hairpin RNAs increased the expression of NF-κB p65, pIKBa, and IKKa. Therefore, Pirh2 suppressed the canonical NF-κB signaling pathway by inhibiting the phosphorylation and subsequent degradation of IKBa to overcome acquired bortezomib resistance in MM cells.     

AKR1B10 accelerates the production of proinflammatory cytokines via the NF-κB signaling pathway in colon cancer

Journal of Molecular Histology - Aldo–keto reductase family one, member B10 (AKR1B10) has been reported to be involved in the tumorigenesis of various cancers. It has been reported that...     

Transgenic inhibition of astroglial NF-κB leads to increased axonal sparing and sprouting following spinal cord injury

We previously showed that Nuclear Factor κB (NF-κB) inactivation in astrocytes leads to improved functional recovery following spinal cord injury (SCI). This correlated with reduced expression of pro-inflammatory mediators and chondroitin sulfate proteoglycans, and increased white matter preservation. Hence we hypothesized that inactivation of astrocytic NF-κB would create a more permissive environment for axonal sprouting and regeneration. We induced both contusive and complete transection SCI in GFAP-Inhibitor of κB-dominant negative (GFAP-IκBα-dn) and wild-type (WT) mice and performed retrograde [fluorogold (FG)] and anterograde [biotinylated dextran amine (BDA)] tracing 8 weeks after injury. Following contusive SCI, more FG-labeled cells were found in motor cortex, reticular formation, and raphe nuclei of transgenic mice. Spared and sprouting BDA-positive corticospinal axons were found caudal to the lesion in GFAP-IκBα-dn mice. Higher numbers of FG-labeled neurons were detected immediately rostral to the lesion in GFAP-IκBα-dn mice, accompanied by increased expression of synaptic and axonal growth-associated molecules. After transection, however, no FG-labeled neurons or BDA-filled axons were found rostral and caudal to the lesion, respectively, in either genotype. These data demonstrated that inhibiting astroglial NF-κB resulted in a growth-supporting terrain promoting sparing and sprouting, rather than regeneration, of supraspinal and propriospinal circuitries essential for locomotion, hence contributing to the improved functional recovery observed after SCI in GFAP-IκBα-dn mice.     

Prolactin Attenuates Neuroinflammation in LPS-Activated SIM-A9 Microglial Cells by Inhibiting NF-κB Pathways Via ERK1/2

Cellular and Molecular Neurobiology - Prolactin (PRL) is a pleiotropic hormone with multiple functions in several tissues and organs, including the brain. PRL decreases lesion-induced microgliosis...     

NOD2 is involved in regulating odontogenic differentiation of DPSCs suppressed by MDP through NF-κB/p65 signaling

Cytotechnology - Dental pulp stem cells (DPSCs) are well known for their capable of both self-renewal and multilineage differentiation. Dental tissue diseases, include caries, are often accompanied...     

The class A macrophage scavenger receptor type I (SR-AI) recognizes complement iC3b and mediates NF-κB activation

The macrophage scavenger receptor SR-AI binds to host tissue debris to perform clearance and it binds to bacteria for phagocytosis. In addition, SR-AI modulates macrophage activation through cell signaling. However, investigation of SR-AI signaling on macrophages is complicated due to its promiscuous ligand specificity that overlaps with other macrophage receptors. Therefore, we expressed SR-AI on HEK 293T cells to investigate its ligand binding and signaling. On 293T cells, SR-AI could respond to E. coli DH5α, leading to NF-κB activation and IL-8 production. However, this requires E. coli DH5α to be sensitized by fresh serum that is treated with heat-inactivation or complement C3 depletion. Anti-C3 antibody inhibits the binding of SR-AI to serum-sensitized DH5α and blocks DH5α stimulation of SR-AI signaling. Further analysis showed that SR-AI can directly bind to purified iC3b but not C3 or C3b. By mutagenesis, The SRCR domain of SR-AI was found to be essential in SR-AI binding to serum-sensitized DH5α. These results revealed a novel property of SR-AI as a complement receptor for iC3b-opsonized bacteria that can elicit cell signaling.