Strength and duration of STAT3 activation determines cellular responses. STAT3 activation patterns and associated outcomes differ between IL6 and IL10 family cytokine-induced signaling. In response to binding of ligand (blue), signaling from gp130 is transient, because the phosphorylated, membrane proximal tyrosine residue (Y, red) provides a binding site for the negative regulator SOCS3. Although SOCS3 is also induced in response to activation of the IL10 receptor family, STAT3 signaling remains sustained, because the IL10 receptor chains lack the corresponding YxxV motif. Similarly, signaling from the mutant gp130Y757F receptor is sustained due to phenylalanine (F) substitution of the Y757 residue (Y759 in human GP130), resulting in exaggerated activation of its down-stream signaling molecules. The range of target genes activated differs between acute and sustained STAT3 activation, most evident in macrophages where the former promotes and the latter suppresses inflammatory response.