Begell House Inc.
Onco Therapeutics
OT
2694-4642
4
2
2013
Preface: NF-κB, Immune System and Chronic Diseases: How Are They Linked?
iv-vi
10.1615/ForumImmunDisTher.2013008395
Subash C.
Gupta
Department of Biochemistry University of Mississippi Medical Center, Jackson, MS
Bharat B.
Aggarwal
Inflammation Research Center, San Diego, CA, USA; Department of Experimental Therapeutics, Division of Cancer Medicine, University of Texas, MD Anderson Cancer Center, Houston, TX 77030, USA
NF-κB and Rheumatoid Arthritis: Will Understanding Genetic Risk Lead to a Therapeutic Reward?
93-110
10.1615/ForumImmunDisTher.2013008408
Robert
Scheinman
University of Colorado Denver, School of Pharmacy, Department of Pharmaceutical Sciences, Aurora, CO 80045
NF-κB
ubiquitin
A20
TNFAIP3
TRAF
REL
single nucleotide polymorphism (SNP)
genome-wide association study (GWAS)
rheumatoid arthritis (RA)
NF-κB has long been known to play an important role in autoimmune diseases such as rheumatoid arthritis (RA). Indeed, as our understanding of how NF-κB is utilized has increased, we have been hard put to find a process not associated with this transcription factor family in some way. However, new data originating, in part, from genome-wide association studies have demonstrated that very specific alterations in components of the NF-κB pathway are sufficient to confer increased risk of developing disease. Here we review the data which have identified specific components of the NF-κB pathway, and consider what is known of their mechanisms of action and how these mechanisms might play into the disease process. In addition, the use of genetic information to predict RA is considered.
Role of NF-Kappa B (NF-κB) in Diabetes
111-132
10.1615/ForumImmunDisTher.2013008396
M.
Indira
Department of Biochemistry, University of Kerala, Kariavattom, Thiruvananthapuram-695 581, Kerala, India
P.A.
Abhilash
Department of Biochemistry, University of Kerala, Kariavattom, Thiruvananthapuram-695 581, Kerala, India
type 1 diabetes
type 2 diabetes
gestational diabetes
nuclear factor kappa B
interleukin 1β
NF kappa B (NF-κB) plays a central and crucial role in the development of diabetes mellitus (DM) and various complications associated with DM. In DM, the NF-κB is activated by a number of pro-inflammatory cytokines, to regulate both survival and death of β-cells, but it is predominantly pro-apoptotic in β-cells. The activation of inducible nitric oxide synthase gene expression and subsequent formation of nitric oxide is also partly involved in the destruction of β-cells. In type 1 diabetes (T1D), interleukin-1 β-induced NF-κB activation causes the apoptosis of β-cells in the pancreas. However, in type 2 diabetes, activated NF-κB induces both apoptosis and insulin resistance. Reactive oxygen species and advanced glycation end products (AGEs) contribute to the progression of a variety of micro- and macro-complications of DM. The interactions of AGEs and their receptor RAGE also lead to the upregulation of NF-κB. Sustained activation of NF-κB induces the systemic inflammation, which is a contributory factor for the development of various diabetic ailments. There are evidences for the activation and involvement of NF-κB in all major diabetic complications such as diabetic cardiomyopathy, retinopathy, nephropathy, and neuropathy. Hence, an NF-κB-based therapeutic approach should be developed for DM. Several antioxidants, including flavonoids, seem to be promising candidates.
RAGE and NF-κB Signaling in Heart Disease
133-147
10.1615/ForumImmunDisTher.2013008768
Hans Christian
Volz
Department of Cardiology, Angiology and Pneumology, University Hospital of Heidelberg, Heidelberg, Germany
Stephan
Schiekofer
Center of Geriatric Medicine, Bezirksklinikum Regensburg, Regensburg, Germany
Ziya
Kaya
Department of Cardiology, Angiology and Pneumology, University Hospital of Heidelberg, Heidelberg, Germany
Hugo A.
Katus
Department of Cardiology, Angiology and Pneumology, University Hospital of Heidelberg, Heidelberg, Germany
Martin
Andrassy
Department of Cardiology, Angiology and Pneumology, University Hospital of Heidelberg, Heidelberg, Germany
innate immunity
inflammatory heart disease
myocarditis
heart failure
cardiomyopathy
HMGB1
Advanced glycation end products (AGEs), S100/calgranulins, high-mobility group box (HMGB)1-protein, amyloid β-peptides, and the family of β-sheet fibrils have been shown to contribute to a number of chronic diseases such as diabetes, amyloidosis, and cancer by promoting cellular dysfunction via binding to the receptor for advanced glycation end products (RAGE). Engagement of RAGE leads to the activation of the nuclear factor (NF)-κB superfamily of transcription factors, which have been implicated in the regulation of numerous cellular processes such as cell survival, apoptosis, and secretion of cytokines in many cell types in immune cells but also cardiomyocytes, endothelial cells, and fibroblasts. However, sustained activation of NF-κB seems to be detrimental and promotes the development of heart failure by eliciting signals that trigger chronic inflammation through enhanced elaboration of various cytokines including tumour necrosis factor a (TNF-α), interleukin-1 (IL-1), and interleukin 6 (IL-6). Furthermore, engagement of RAGE appears to lead to prolonged NF-κB-mediated activation overwhelming endogenous autoregulatory feedback inhibition loops. The underlying mechanisms that account for the multifaceted and differential effects of NF-κB on cardiac cells are presently not fully understood. In this review, we will focus on the role of RAGE as a master switch of inflammation by converting a brief pulse of cellular activation to sustained cellular dysfunction. Furthermore, we discuss how duration of activation and cellular context may explain mechanistically the differential effects of NF-κB signaling in the heart.
The Role of NF-κB in Muscular Dystrophy
149-160
10.1615/ForumImmunDisTher.2013008386
Jonathan D.
Proto
Growth and Development Laboratory, University of Pittsburgh, Pittsburgh, PA
Aiping
Lu
Growth and Development Laboratory, University of Pittsburgh, Pittsburgh, PA
Bing
Wang
Molecular Therapy Laboratory, Stem Cell Research Center, Department of Orthopaedic Surgery, University of Pittsburgh, Pittsburgh, PA
Johnny
Huard
University of Texas Health Science Center at Houston Medical School Department of Orthopaedic Surgery 1881 East Road South Campus Research Building #3 Houston, TX 77054
NF-κB
Duchenne muscular dystrophy (DMD)
inflammation
Aberrant activation of the nuclear factor−kappa B (NF-κB) pathway is associated with the fatal genetic muscle disease, Duchenne muscular dystrophy (DMD). NF-κB has been identified as a key player in the negative effects of chronic inflammation, which characterizes dystrophic skeletal muscle. This includes the suppression of myogenesis, which leads to decreased muscle regeneration and the exacerbation of muscular dystrophy. Several hypotheses have been proposed to explain the upregulation of NF-κB activity, and although differing significantly, they all point to the classical activation pathway, regulated by the inhibitor of kappa-B kinase (IKK). The dystrophic phenotype has been found to be significantly improved in transgenic dystrophic (mdx) mice with lowered NF-κB activity. Furthermore, several pharmacologic strategies of NF-κB blockade have demonstrated efficacy in DMD animal models, suggesting that this pathway has the potential to be a therapeutic target in human DMD patients.
Role of NF-κB in Neurodegenerative Diseases
161-179
10.1615/ForumImmunDisTher.2013008385
Ronny
Haenold
Leibniz-Institute for Age Research−Fritz-Lipmann-Institute (FLI), Beutenberg Strasse 11, 07745 Jena, Germany
Alexandra
Kretz
Hans Berger Department of Neurology, University Hospital Jena, Friedrich-Schiller University, Erlanger Allee 101, 07747 Jena, Germany
Falk
Weih
Leibniz-Institute for Age Research−Fritz-Lipmann-Institute (FLI), Beutenberg Strasse 11, 07745 Jena, Germany
NF-κB
central nervous system (CNS)
neuropathology
neurodegeneration
Besides the constitutively active form of nuclear factor-κB (NF-κB), which is required for neuronal plasticity, inducible activation of this transcription factor in neuronal and glial cells is frequently associated with neurodegenerative diseases. Here, we summarize current findings on the role of NF-κB in initiation, progression, and mitigation of acute or chronic neuropathologies with a special emphasis on subunit- and cell-type-specific effects. We discuss disease-specific functions of NF-κB and draw conclusions with respect to common regulatory mechanisms. A special focus will be on how NF-κB-dependent gene expression becomes critical for neuronal cell fate decision. Macroglial NF-κB activation will be addressed in the context of chronic neurodegeneration, neuroinflammation, and scar formation. Further, the complex role of NF-κB in microglia and immune cells for CNS autoimmune responses and tissue damage is covered. Finally, we will review case reports and studies on transgenic mouse lines to illustrate how mutations in genes encoding constituents of the NF-κB signaling pathway are linked to CNS dysfunction and hereditary mental retardation.
Role of NF-κB in Tumorigenesis
181-196
10.1615/ForumImmunDisTher.2013008382
Muthu K.
Shanmugam
Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597
Alan P.
Kumar
Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597; Cancer Science Institute of Singapore, National University of Singapore, Centre for Translational Medicine, Singapore 117599
Benny K. H.
Tan
Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597
Gautam
Sethi
Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597; Cancer Science Institute of Singapore, National University of Singapore, Centre for Translational Medicine, Singapore 117599
NF-κB
cancer
inflammation
proliferation
apoptosis
angiogenesis
Persistent activation of the pro-inflammatory transcription factor nuclear factor-κB (NF-κB) is frequently observed in several human malignancies and can drive the processes of tumor initiation, oncogenic transformation, and malignant progression. Once activated, this master transcription factor regulates the expression of numerous genes involved in proliferation, survival, metastasis, angiogenesis, chemoresistance, and radioresistance. Thus, novel pharmacological agents that can suppress constitutive and/or inducible NF-κB activation have the potential for cancer therapy. In this review, we describe in detail the pleiotropic molecular mechanisms of aberrant NF-κB activation and also discuss various therapeutic strategies employed to suppress deregulated activation of this important oncogenic transcription factor in cancer.