Page 243 - Veterinary Immunology, 10th Edition

JAK-STAT Pathway
VetBooks.ir Almost 40 cytokines use the JAK-STAT pathway, including IL-4, IL-

7, IL-11, IL-12, IL-13, and IL-31, leptin, GM-CSF, and IFN-γ. These
ligands use group I cytokine receptors that consist of two identical
transmembrane proteins. When a cytokine binds to its receptor the

two proteins come together. This dimerization leads in turn to
phosphorylation of two tightly associated JAK proteins. These
activated JAK molecules then phosphorylate STAT proteins. The
phosphorylated STAT proteins dissociate from JAK and move to
the nucleus, where they act as transcription factors and induce the

expression of target genes. There are four JAK and seven STAT
family members currently recognized. A specific JAK-STAT
combination is paired with each cytokine receptor. For example,

hematopoietic growth factor receptors usually use JAK2. Receptors
with the common γ chain preferentially use JAK1 and JAK3. The
IFN-γ receptor uses JAK1 and JAK2. The IL-4R uses JAK1 and
JAK3. Presumably the genes turned on by this signaling depend on
these specific combinations of JAK and STAT as well as the cell type

involved (Box 8.2).

Box 8.2

Inhibition of JAK-STAT Signaling

Inhibition of JAK-STAT signaling can have immunosuppressive
and antiinflammatory effects. This may be useful in suppressing
unwanted immune responses or inflammation. Drugs directed
against specific JAK proteins can have profound antiinflammatory

responses. For example, oclacitinib (Apoquel) is a synthetic
selective inhibitor of JAK1 and JAK3. As a result, it blocks signal
transduction and hence inhibits the itching caused by IL-31
(Chapter 30). Specifically, it is used for the treatment of severe itch

(pruritus) in dogs with allergic dermatitis including flea and food
allergies, atopic dermatitis, and contact dermatitis (Chapters 30
and 33).

Although the pathways described above are of greatest
importance in cells of the immune system, many other transcription

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