NF-κB pathway consists of canonical and non-canonical pathways. The canonical NF-κB is activated by various stimuli, transducing a quick but transient transcriptional activity, to regulate the expression of various proinflammatory genes and also serve as the critical mediator for inflammatory response. Meanwhile, the activation of the non-canonical NF-κB pathway occurs through a handful of TNF receptor superfamily members. Since the activation of this pathway involves protein synthesis, the kinetics of non-canonical NF-κB activation is slow but persistent, in concordance with its biological functions in the development of immune cell and lymphoid organ, immune homeostasis and immune response. The activation of the canonical and non-canonical NF-κB pathway is tightly controlled, highlighting the vital roles of ubiquitination in these pathways. Emerging studies indicate that dysregulated NF-κB activity causes inflammation-related diseases as well as cancers, and NF-κB has been long proposed as the potential target for therapy of diseases. This review attempts to summarize our current knowledge and updates on the mechanisms of NF-κB pathway regulation and the potential therapeutic application of inhibition of NF-κB signaling in cancer and inflammatory diseases.

The transcriptional regulator STAT3 has key roles in vertebrate development and mature tissue function including control of inflammation and immunity. Mutations in human STAT3 associate with diseases such as immunodeficiency autoimmunity and cancer. Strikingly, however, either hyperactivation or inactivation of STAT3 results in human disease, indicating tightly regulated STAT3 function is central to health. Here, we attempt to summarize information on the numerous and distinct biological actions of STAT3, and highlight recent discoveries, with a specific focus on STAT3 function in the immune and hematopoietic systems. Our goal is to spur investigation on mechanisms by which aberrant STAT3 function drives human disease and novel approaches that might be used to modulate disease outcome.

Granulocyte colony-stimulating factor (G-CSF) mediates "emergency" granulopoiesis during infection, a process that is mimicked by clinical G-CSF use, yet we understand little about the intracellular signaling cascades that control demand-driven neutrophil production. Using a murine model with conditional deletion of signal transducer and activator of transcription 3 (STAT3) in bone marrow, we investigated the cellular and molecular mechanisms of STAT3 function in the emergency granulopoiesis IntroductionNeutrophils serve a critical function in the innate immune system by maintaining a frontline defense against bacterial and fungal pathogens. However, precise control of circulating neutrophil amounts is important in preserving a balance between effective immunity versus immunosuppression or inflammation. For example, congenital or therapy-induced neutropenias render persons sensitive to life-threatening infections, whereas neutrophil overproduction or hyperactivation contributes to inflammation and, potentially, autoimmunity. 1,2 To maintain appropriate neutrophil numbers, the process of granulopoiesis is tightly regulated. In steady state conditions, the bone marrow continuously produces granulocytes and stores a reserve of mature neutrophils, whereas circulating neutrophil numbers are maintained within a narrow range (3.5-4.5 ϫ 10 9 /L for humans and approximately 0.488 ϫ 10 9 /L for mice). 3 The neutrophil production pathway is responsive to environmental stresses such as infection, which stimulate a rapid increase in granulopoiesis, enhanced neutrophil migration from bone marrow, and a subsequent rise in peripheral neutrophils (eg, circulating neutrophils Ͼ 8 ϫ 10 9 /L in human infection). 4 Neutrophil development from hematopoietic stem cells (HSCs) is guided by granulocyte colony-stimulating factor (G-CSF), which activates a high-affinity type I cytokine receptor, G-CSF receptor (G-CSFR), expressed on HSCs, myeloid progenitor cells, granulocyte precursors, and mature neutrophils. 5 In homeostatic conditions, G-CSF-G-CSFR signals maintain mature neutrophil numbers in circulation by regulating the proliferation and differentiation of myeloid progenitors as well as survival of postmitotic bone marrow neutrophils. 6,7 During infection, G-CSF serum levels can increase 10-to 20-fold, stimulating enhanced neutrophil production in the bone marrow and neutrophil mobilization to the peripheral blood. 8 This response, termed "emergency" or demanddriven granulopoiesis, is characterized by enhanced cell-cycle progression of granulocyte precursors and efflux of mature neutrophils from the bone marrow, relative to steady state conditions. 9 The signal transduction pathways that regulate emergency granulopoiesis are of significant interest because G-CSF is used therapeutically to increase circulating neutrophil counts; however, the underlying mechanisms directing G-CSF-responsive myeloid progenitor expansion are poorly understood.Janus kinase and signal transducer and activator of transcription (STAT) pathway components a...

Activating mutations of K-ras are the most common oncogenic alterations found in lung cancer. Unfortunately, attempts to target K-ras mutant lung tumors have thus far failed, clearly indicating the need for new approaches in patients with this molecular profile. We have previously shown NF-κB activation, release of IL-6, and activation of its responsive transcription factor STAT3 in K-ras mutant lung tumors, which was further amplified by the tumor enhancing effect of chronic obstructive pulmonary disease (COPD)-type airway inflammation. These findings suggest an essential role for this inflammatory pathway in K-ras mutant lung tumorigenesis and its enhancement by COPD. Therefore, here we blocked IL-6 using a monoclonal anti-IL-6 antibody in a K-ras mutant mouse model of lung cancer in the absence or presence of COPD-type airway inflammation. IL-6 blockade significantly inhibited lung cancer promotion, tumor cell intrinsic STAT3 activation, tumor cell proliferation, and angiogenesis markers. Moreover, IL-6 inhibition reduced expression of pro-tumor type 2 molecules (Arginase 1, Fizz 1, Mgl, and IDO), number of M2 type macrophages and G-MDSCs, and pro-tumor T-regulatory/T helper 17 cell responses. This was accompanied by increased expression of anti-tumor type 1 molecule (Nos2), and anti-tumor T helper 1/CD8 T cell responses. Our study demonstrates that IL-6 blockade not only has direct intrinsic inhibitory effect on tumor cells, but also re-educates the lung microenvironment toward an anti-tumor phenotype by altering the relative proportion between pro-tumor and anti-tumor immune cells. This information introduces IL-6 as a potential druggable target for prevention and treatment of K-ras mutant lung tumors.

Nitric oxide (NO) produced by macrophages is toxic to host tissues and invading pathogens and its regulation is therefore essential to suppress host cytotoxicity. Macrophage arginase 1 (Arg1) inhibits the production of NO by competing with NO synthases for arginine, the common substrate of NO synthases and arginases. Two signal transduction pathways control the production of Arg1 in macrophages. First, a pathway dependent on the Toll-like receptor (TLR) adaptor protein myeloid differentiation marker 88 (MyD88) induces the expression of Arg1 in intracellular infections, whereas a second pathway, which is dependent on signal transducer and activator of transcription 6 (STAT6) is required for the expression of Arg1 in alternatively-activated macrophages. We found that mycobacteria-infected macrophages produced soluble factors, including interleukin-6 (IL-6), IL-10, and granulocyte colony-stimulating factor (G-CSF), that induced the expression of Arg1 in an autocrine-paracrine manner. We further established that Arg1 expression was controlled by the MyD88-dependent production of IL-6, IL-10, and G-CSF rather than by cell-intrinsic MyD88 signaling to Arg1. Our data reveal that the MyD88-dependent pathway that induces expression of Arg1 after infection by mycobacteria requires the activation of STAT3 and may result in the development of an immunosuppressive niche in granulomas because of the induced production of Arg1 in surrounding uninfected macrophages.* This manuscript has been accepted for publication in Science Signaling. This version has not undergone final editing. Please refer to the complete version of record at http://www.sciencesignaling.org/. The manuscript may not be reproduced or used in any manner that does not fall within the fair use provisions of the