Colonic macrophages (cMPs) are important for intestinal homeostasis as they kill microbes and yet produce regulatory cytokines. Activity of the NLRP3 (nucleotide-binding leucine-rich repeat-containing pyrin receptor 3) inflammasome, a major sensor of stress and microorganisms that results in pro-inflammatory cytokine production and cell death, must be tightly controlled in the intestine. We demonstrate that resident cMPs are hyporesponsive to NLRP3 inflammasome activation owing to a remarkable level of posttranscriptional control of NLRP3 and pro-interleukin-1β (proIL-1β) protein expression, which was also seen for tumor necrosis factor-α and IL-6, but lost during experimental colitis. Resident cMPs rapidly degraded NLRP3 and proIL-1β proteins by the ubiquitin/proteasome system. Finally, blocking IL-10R-signaling in vivo enhanced NLRP3 and proIL-1β protein but not mRNA levels in resident cMPs, implicating a role for IL-10 in environmental conditioning of cMPs. These data are the first to show dramatic posttranscriptional control of inflammatory cytokine production by a relevant tissue-derived macrophage population and proteasomal degradation of proIL-1β and NLRP3 as a mechanism to control inflammasome activation, findings which have broad implications for our understanding of intestinal and systemic inflammatory diseases.