Cellular inhibitor of apoptosis proteins (cIAPs) have emerged as important 
anti-cell death mediators, particularly in cancer. Although they are known to be 
expressed in immune tissue, their specific immune function remains unclear. We 
observed that degradation of cIAPs with SMAC mimetic (SM) results in death of 
primary bone-marrow-derived macrophages. SM-induced death of macrophages 
occurred by programmed necrosis (necroptosis), which was dependent on TNF 
receptor expression. Consistent with necroptosis, SM-induced death of 
macrophages was abrogated by inhibition of receptor interacting protein 1 (Rip1) 
kinase signaling or by receptor interacting protein 3 (Rip3) knockdown. 
SM-induced necroptosis was also dependent on inhibition of SM-induced apoptosis 
due to the expression of the endogenous caspase inhibitor, xIAP. We found that 
cIAPs limit Rip3, and to a lesser extent Rip1, expression via 
post-transcriptional mechanisms, leading to inhibition of the Rip1-Rip3 death 
complex (necrosome). Reduced cIAP activity in vivo, via SM treatment or specific 
knockout of either cIAP, resulted in elevated macrophage cell death and 
compromised control of an intracellular bacterium, Listeria monocytogenes. These 
results show that cIAPs have an important role in limiting programmed necrosis 
of macrophages, which facilitates effective control of a pathogen.