STAT3 is recruited directly to the receptor complex via either of the two tyrosine residues in the IL10R1 cytoplasmic domain (Y446 and Y496) that become phosphorylated in response to IL-10 (Weber-Nordt et al. 1996, Riley et al. 1999). Overexpression of a dominant negative mouse Stat3 mutant or an inducibly-active form of mouse Stat3 demonstrated that Stat3 activation is necessary and sufficient to mediate inhibition of macrophage proliferation by IL-10 (O'Farrell et al. 1998) at least in part via enhancement of CDKN2D (INK4d) and CDKN1A (CIP1) expression (O'Farrell et al. 2000). In contrast, the Stat3 mutant did not detectably impair IL-10's ability to inhibit LPS-induced monokine production suggesting that IL10 inhibition of macrophage proliferation and monokine production are the result of two distinct signaling pathways (O'Farrell et al. 1998). Stat3 conditional knockout mice develop chronic enterocholitis and have macrophages that show no response to IL10 (Riley et al. 1999, Takeda et al. 1999).