When the same experiments were performed in mice lacking i-proteasomes, there was accumulation of oxidized proteins, and higher levels of PF-02341066 purchase apoptosis; and in the EAE model, higher clinical scores of the disease. These data support the hypothesis that i-proteasomes play a protective role against toxic effects induced by protein aggregates formed when cells are subjected to the inflammatory millieu [81]. Nevertheless, the question of whether and how the UPR intersects with i-proteasomes remains open. Both conditions observed in the study (stimulation by pro-inflammatory cytokines and accumulation of misfolded proteins) are potential ER stressors. The protective role of UPR at the face of

protein overload triggered by the innate immune response appears to be conserved through HDAC inhibitor evolution.

In Caenorhabditis elegans, protective immunity against Pseudomonas aeruginosa is dependent on PMK-1, an ortholog of the mammalian p38 MAP kinase [82]. Infection by P. aeruginosa causes ER stress, inducing XBP-1 splicing. Infection by these bacteria was lethal for a XBP-1 loss-of-function mutant. Surprisingly, the lethal outcome of the infection in XBP-1 mutants was reversed when PMK-1 was disrupted. Furthermore, hyperactivation of PMK-1 caused larval mortality on the XBP-1 mutants even in the absence of the pathogen. Unexpectedly, mutants for ATF6 and PEK1 (homologue during of PERK) developed normally and did not show a detrimental phenotype. The study concludes that although the innate response promotes resistance to this pathogen, it also represents a source of ER stress, demanding a compensatory

activity of the UPR for the development of C. elegans larvae [83]. This hypothesis is further supported by the observation that when C. elegans larvae were stimulated with a pore forming bacterial toxin, PMK-1 was activated as a defense mechanism. The UPR pathway was activated through IRE1/XBP-1 and ATF6. XBP-1 and ATF6 loss-of-function mutants were more susceptible to the toxin, in a SEK1– (MAPKK upstream of PMK-1) and PMK1-dependent manner [84] (Fig. 3). The first report showing that the XBP-1 transcription factor was highly expressed by pre-pro-B cell and plasma cell lines [52] rouse the interest to study the role of XBP-1 in B cell biology. XBP-1 is a necessary transcription factor for B cell terminal differentiation into plasma cells [85]. The disruption of XBP-1 in mice leads to mortality in uterus caused by anaemia due to liver hypoplasia [86]. XBP1−/−RAG2−/− chimera mice develop normally and with normal numbers of T and B lymphocytes. These animals present lower serum immunoglobulin levels when compared with their wild-type littermates. Nevertheless, there are no differences in proliferation and isotype class switch by XBP1-deficient B cells, and no defects in germinal centre formation in XBP1-deficient mice.