Investigating the role of the JAK/STAT and MAPK ... - UCL Discovery

evidenced by the prolonged STAT3 phosphorylation seen in SOCS3 deficient cells following
IL-6 treatment (Lang et al., 2003). Prolonged STAT3 activation is therefore instrumental in
the anti-inflammatory response and leads to suppression of pro-inflammatory cytokine
production by toll-like receptors (Fig 1.8). Moreover, IL-6 treatment of macrophages
deficient in SOCS3 or harboring mutation of the SOCS3 binding site on gp130 produces an
anti-inflammatory response, clearly showing that the duration of STAT3 activity determines
the differing biological responses to IL-6 and IL-10 (Yasukawa et al., 2003). This was
confirmed by studies demonstrating an anti-inflammatory response using modified leptin and
erythropoietin receptors which could activate STAT3 but not bind SOCS3 (El Kasmi et al.,
2006) and by using a constitutively active STAT3 which also mediates an anti-inflammatory
response (Williams et al., 2007). Thus it seems that regulation of the duration of STAT3
phosphorylation by SOCS3 determines the outcome of anti-inflammatory cytokine signaling.
Fig 1.8. Inhibition of STAT signaling by SOCS3. SOCS3 expression is induced by cytokines TLR
ligands and cAMP. SOCS3 blocks STAT3 and STAT1 activation by the IL-6 pathway but does not
affect IL-10 signalling. SOCS3 therefore inhibits pro-inflammatory IL-6 activity while allowing antiinflammatory
IL-10 signalling through prolonged STAT3 activation. An unknown protein or proteins
(x) is thought to be responsible for STAT3 mediated inhibition of pro-inflammatory responses
induced from TLRs. Taken from Yoshimura et al., 2007.
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