The role of the transcription factor NF-kB in the pathogenesis of inflammation and carcinogenesis. Modulation capabilities

The nuclear factor kappa B (NF-kB) signaling module is a complex and highly interconnected molecular network with important functions in all nucleated cells. Most chronic diseases caused by lifestyle factors appear to be related to inflammation. The NF-kB plays a major role in the pathogenesis of the inflammation and its intimate molecular mechanism. This transcription factor participates in the evolution of diabetes and its complications. In T1D (Type 1 Diabetes), proinflammatory cytokines such as interleukin-1β (IL-1β), tumor necrosis factor (TNF), and CD40L secreted by immune cells in islets induce the activation of NF-kB in β-cells through both canonical and noncanonical roads. NF-kB activation increases the expression of genes, including TNF-α, IL-1β, IL-6, MCP-1, and ICAM-1, that initiate and promote atherosclerosis. In particular, the severity and lethality of acute lung injury or acute respiratory distress syndrome (ALI/ARDS) caused by pneumonia or sepsis is primarily associated with an NF-kB-mediated “cytokine storm,” in which massive polymorphonuclear (PMN) extravasation and the subsequent release of cytokines cause rapid deterioration due to widespread inflammation and coagulation. Nuclear translocation of NF-kB p65 can induce the transcription of several genes involved in the induction of EMT (epithelial-to-mesenchymal transition). This has been confirmed in various types of cancer, including brain, breast, lung, and gastric cancer. Cutaneous T-cell lymphoma (CTCL) encompasses a group of lymphoproliferative disorders characterized by invasive neoplastic T cells in the skin and various clinical prognoses. In the early stages of CTCL, NF-kB activation and cell proliferation are stimulated by the autocrine production of TNFα, leading to increased NF-kB activation and resistance to apoptosis. Bladder cancer is the second most common genitourinary cancer and is often recurrent and/or chemoresistant after tumor resection. NF-kB is a transcription factor that plays a critical role in normal physiology and bladder cancer. Bladder cancer patients have pathologically active NF-kB induced by proinflammatory cytokines, chemokines, and hypoxia, enhancing carcinogenesis and progression of the disease.