Regulation of innate immunity by MAPK dual-specificity phosphatases: knockout models reveal new tricks of old genes

Throughout evolution, mammals have developed an elaborate network of positive and negative regulatory mechanisms, which provide balance between defensive measures against bacterial and viral pathogens and protective measures against unwarranted destruction of the host by the activated immune system. Kinases and phosphatases encompassing the MAPK pathway are key players in the orderly action of pro- and anti-inflammatory processes, forming numerous promiscuous interactions. Several lines of evidence demonstrate that the phosphorylation and activation status of kinases in the MAPK system has crucial impact on the outcome of downstream events that regulate cytokine production. At least 13 members of the family of dual-specificity phosphatases (DUSP) display unique substrate specificities for MAPKs. Despite the considerable amount of information obtained about the contribution of the different DUSP to MAPK-mediated signaling and innate immunity, the interpretation of available data remains problematic. The in vitro and ex vivo findings are often complicated by functional redundancy of signaling molecules and do not always accurately predict the situation in vivo. Until recently, DUSP research has been hampered by the lack of relevant mammalian knockout (KO) models, which is a powerful tool for delineating in vivo function and redundancy in gene families. This situation changed dramatically over the last year, and this review integrates recent insights into the precise biological role of the DUSP family in innate immunity gained from a comprehensive analysis of mammalian KO models.