Interleukin-1α (IL-1α) and IL-1β are inflammatory cytokines with important roles in health and disease. They trigger the same receptor and elicit comparable cellular responses but, for poorly understood reasons, are not redundant in vivo. Here, we decoupled IL-1α and IL-1β functions that drive protective responses against invasive infection with group A Streptococcus . IL-1β was essential for pathogen clearance, hence resistance to infection, by inducing granulocyte colony-stimulating factor at the infection site and establishing emergency granulopoiesis. In contrast, IL-1α governed reprogramming of liver metabolic pathways associated with tolerance to infection. The IL-1α−dominated hepatic regulation corresponded to high IL-1α levels in the liver during infection. Conversely, IL-1β was critical for the regulation of the spleen transcriptome, which correlated with ample IL-1β expression in this tissue. The results identify distinct and organ-specific roles of IL-1α versus IL-1β and implicate spatial restriction of their expression and bioavailability during infection as the underlying mechanism.

Regulated changes in mRNA stability are critical drivers of gene expression adaptations to immunological cues. mRNA stability is controlled mainly by RNA-binding proteins (RBPs) which can directly cleave mRNA but more often act as adaptors for the recruitment of the RNA-degradation machinery. One of the most prominent RBPs with regulatory roles in the immune system is tristetraprolin (TTP). TTP targets mainly inflammation-associated mRNAs for degradation and is indispensable for the resolution of inflammation as well as the maintenance of immune homeostasis. Recent advances in the transcriptome-wide knowledge of mRNA expression and decay rates together with TTP binding sites in the target mRNAs revealed important limitations in our understanding of molecular mechanisms of TTP action. Such orthogonal analyses lead to the discovery that TTP binding destabilizes some bound mRNAs but not others in the same cell. Moreover, comparisons of various immune cells indicated that an mRNA can be destabilized by TTP in one cell type while it remains stable in a different cell linage despite the presence of TTP. The action of TTP extends from mRNA destabilization to inhibition of translation in a subset of targets. This article will discuss these unexpected context-dependent functions and their implications for the regulation of immune responses. Attention will be also payed to new insights into the role of TTP in physiology and tissue homeostasis.