NF-κB (p50/p65) Pathway

Nuclear factor kappa B (NF-κB) is a transcription factor that is associated with inflammation. Without stimulus, NF-κB is repressed by inhibitor of kappa B (IκB) proteins. Upon stimulation by TNF, IL-1, and/or pathogen-associated molecular patterns (e.g. LPS), adaptor proteins like MyD88 and TRAF will signal for the activation of inhibitor of kappa B kinase (IκBK), which goes on to phosphorylate either IκB (canonical pathway) or the p100 subunit of NF-κB (alternative pathway). The pathway of activation is dictated by the signal: TNF, IL-1 and TLR stimulation activate the classical pathway, while CD40L and BAFF activate the alternative pathway. In the classical pathway, phosphorylated IκB is ubiquitinated and then degraded, allowing for NF-κB to enter the nucleus and turn on transcription of genes for cytokines like TNFα and IL-1. The alternative pathway involves activation of the NF-κB-inducing kinase (NIK), which turns on IκB kinase-α (IKKα), leading to p100 phosphorylation.

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