Page 238 - Veterinary Immunology, 10th Edition

antiapoptotic proteins, inducible enzymes such as iNOS and
VetBooks.ir cyclooxygenase-2 (COX-2), as well as IκB. This newly synthesized

IκB will eventually bind and suppress NF-κB activation. Molecules
or organisms that block the destruction of IκB have

antiinflammatory and immunosuppressive effects. For example,
corticosteroids stimulate the production of excess IκB, whereas
some bacteria can block its degradation. Either way, the activation
of cells and the development of inflammation and immune

responses may be blocked.
An example of the importance of the NF-κB pathway is seen
when macrophages respond to a PAMP that binds to their TLRs
(Fig. 8.10). This immediately causes the receptor to dimerize. As a

result, it binds several adaptor molecules, of which one, myeloid
differentiation primary response gene 88 (MyD88), is the most
important (Chapter 2). When MyD88 binds to the TLR, it also binds
two kinases called IRAK-1 and IRAK-4. IRAK-4 activates IRAK-1,

and these in turn recruit TRAF6. TRAF6 and other proteins then
activate the IKK complex. Activation of IKK phosphorylates IκB,
causing its destruction and the release of active NF-κB. The NF-κB
in turn enters the nucleus and activates the genes that encode

precursors of TNF-α, IL-1β, and caspase-1. Caspase-1 activates
these newly produced cytokines that then trigger inflammation.

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