Inflammatory Signaling Pathways Triggered by NFkB

Numerous proinflammatory mediators, such as IL1 and TNF-a, induce nuclear translocation of NFkB, which in turn activates transcription of gene products involved in inflammatory response, angiogenesis, and cell adhesion. NFkB promotes the expression of cell adhesion molecules (intercellular adhesion molecule (ICAM)-1, vascular cell adhesion molecule (VCAM)-1, E selectin, tenascin C), VEGF, and of matrix metalloproteases (MMP)-2 and -9, responsible for degradation of the extracellular matrix.63 This transcription factor is also involved in transcription of genes coding for enzymes such as inducible nitric oxide synthase (iNOS), cyclooxygenase (COX)-2, 5- and 12-lipooxygenase (LOX), chemokines, and cytokines (IL1 and TNF-a). COX-2 is upregulated in aggressive colorectal cancers and has been found to promote angiogenesis. Mediators such as nitric oxide, prostaglandins, IL1, or TNF-a are involved in the regulation of blood pressure, platelet aggregation, and body temperature. Moreover, NFkB is also important in the transcription of genes coding for several acute-phase proteins.

NFkB constitutive activity seems to play a role in chronic inflammatory diseases such as inflammatory bowel disease, Crohn's disease, ulcerative colitis, rheumatoid arthritis, and asthma.33 NFkB activation in chronic inflammation may have a role in tumor initiation, since the antiapoptotic genes activated by this transcription factor may contribute to the survival of altered cells that would otherwise be committed to apoptosis and thereby allow formation of precancerous lesions. For instance, Helicobacter pylori infections or constitutive activation of the IL1 gene, both triggering NFkB activation, are risk factors for the development of gastric cancer.64,65 Constitutive NFkB activation may also be responsible for the development of colitis-associated cancer by patients suffering from inflammatory bowel disease, ulcerative colitis, or Crohn's disease.66-68

NFkB and its target genes are potent antiapoptotic and proinflammatory mediators and are thus involved in various pathologies such as chronic inflammatory diseases and cancers. Inhibition of NFkB activation is a very promising therapeutic approach to fight those pathologies. Some inhibitors are already potent NFkB modulators in clinical use, while others remain benchtop compounds still in process. Nevertheless, a better understanding of the different steps leading to NFkB transcriptional activation in different cancer types will permit increased accuracy in the design of various inhibitors, allowing precise targeting of the chosen step.

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