Interleukin 17C (IL-17C) is a member of the IL-17 family that is selectively induced in epithelia by bacterial challenge and inflammatory stimuli. Here we show that IL-17C functioned in a unique autocrine manner, binding to a receptor complex consisting of the receptors IL-17RA and IL-17RE, which was preferentially expressed on tissue epithelial cells. IL-17C stimulated epithelial inflammatory responses, including the expression of proinflammatory cytokines, chemokines and antimicrobial peptides, which were similar to those induced by IL-17A and IL-17F. However, IL-17C was produced by distinct cellular sources, such as epithelial cells, in contrast to IL-17A, which was produced mainly by leukocytes, especially those of the T(H)17 subset of helper T cells. Whereas IL-17C promoted inflammation in an imiquimod-induced skin-inflammation model, it exerted protective functions in dextran sodium sulfate-induced colitis. Thus, IL-17C is an essential autocrine cytokine that regulates innate epithelial immune responses.

Many important signaling pathways rely on multiple ligands. It is unclear if this is a mechanism of safeguard via redundancy or if it serves other functional purposes. In this study, we report unique insight into this question by studying the activin receptor-like kinase 1 (ALK1) pathway. Despite its functional importance in vascular development, the physiological ligand or ligands for ALK1 remain to be determined. Using conventional knockout and specific antibodies against bone morphogenetic protein 9 (BMP9) or BMP10, we showed that BMP9 and BMP10 are the physiological, functionally equivalent ligands of ALK1 in vascular development. Timing of expression dictates the in vivo requisite role of each ligand, and concurrent expression results in redundancy. We generated mice (Bmp10) in which the coding sequence of Bmp9 replaces that of Bmp10. Surprisingly, analysis of Bmp10 9/9 mice demonstrated that BMP10 has an exclusive function in cardiac development, which cannot be substituted by BMP9. Our study reveals context-dependent significance in having multiple ligands in a signaling pathway.heart homeostasis | heart development | hereditary hemorrhagic telangiectasia | angiogenesis H ereditary hemorrhagic telangiectasia (HHT) is a genetic disorder with multisystemic vascular dysplasia (1, 2). The underlying cause of the major clinical symptoms of HHT is a vascular anomaly referred to as arteriovenous malformation (AVM). HHT types 1 and 2 are the two major forms of HHT caused by heterozygous mutations in genes encoding endoglin (ENG) and ALK1 [also know as activin A receptor type II-like 1 (ACVRL1)], respectively (3). ALK1, a type I receptor of the TGFβ receptor family, is predominantly expressed in endothelial cells (4). Genetic studies have revealed important roles of ALK1 during vascular development. In the absence of ALK1, mouse embryos die during midgestation with profound vessel dilation and severe AVM (5, 6). The importance of ALK1 signaling in vascular morphogenesis is also highlighted by its intimate link to other essential pathways in vascular biology, including Notch signaling (7).Whereas genetic studies have established ALK1 signaling as an essential pathway regulating vascular development, the physiological ligand(s) responsible for ALK1 activation remains to be definitively determined. Early studies suggest that TGFβs signal through ALK1 and ALK5 in endothelial cells (8). David et al., however, show that bone morphogenetic protein 9 (BMP9) [also known as growth differentiation factor 2 (GDF2)] and BMP10, but not TGFβs, are capable of binding recombinant ALK1 (9, 10). BMP10 displays cardiac-specific expression (11). Bmp10-deficient mice die between embryonic day 9.5 (E9.5) and E10.5 with profound defects in cardiac development (12). Interestingly, no defects in vascular development have been described in Bmp10-deficient mice (12), leading to the speculation that the role of BMP10 may be limited to the cardiac tissue. On the other hand, it has been shown that BMP9, a liver-specific BMP, is present at signi...

Reactive oxygen species (ROS) produced by phagocytes are essential for host defence against bacterial and fungal infections. Individuals with defective ROS production machinery develop chronic granulomatous disease. Conversely, excessive ROS can cause collateral tissue damage during inflammatory processes and therefore needs to be tightly regulated. Here we describe a protein, we termed negative regulator of ROS (NRROS), which limits ROS generation by phagocytes during inflammatory responses. NRROS expression in phagocytes can be repressed by inflammatory signals. NRROS-deficient phagocytes produce increased ROS upon inflammatory challenges, and mice lacking NRROS in their phagocytes show enhanced bactericidal activity against Escherichia coli and Listeria monocytogenes. Conversely, these mice develop severe experimental autoimmune encephalomyelitis owing to oxidative tissue damage in the central nervous system. Mechanistically, NRROS is localized to the endoplasmic reticulum, where it directly interacts with nascent NOX2 (also known as gp91(phox) and encoded by Cybb) monomer, one of the membrane-bound subunits of the NADPH oxidase complex, and facilitates the degradation of NOX2 through the endoplasmic-reticulum-associated degradation pathway. Thus, NRROS provides a hitherto undefined mechanism for regulating ROS production--one that enables phagocytes to produce higher amounts of ROS, if required to control invading pathogens, while minimizing unwanted collateral tissue damage.

SUMMARYThe effect of prenatal exposure to bisphenol A (BPA) on the immune system in mice was investigated. Virgin female mice were fed varying doses of BPA, on a daily basis, over a period of 18 days commencing on the day of pairing with stud males (day 0). On day 77, their male offspring of 8 weeks were immunized with hen egg lysozyme (HEL). Three weeks later, anti-HEL immunoglobulin G (IgG) in sera, and proliferative responses of spleen cells to the antigen, were measured. Anti-HEL IgG2a and interferon-c (IFN-c), secreted from splenic lymphocytes, were measured as indicators of T helper 1 (Th1) immune responses, while anti-HEL IgG1 and interleukin-4 (IL-4) were measured as indicators of Th2 responses. The results showed that fetal exposure to BPA was followed by significant increases in anti-HEL IgG as well as antigenspecific cell proliferation. Both Th1 responses (including anti-HEL IgG2a and IFN-c production) and Th2 responses (including anti-HEL IgG1 and IL-4 production) were augmented by prenatal exposure to BPA, although the augmentation of Th1 responses appeared to be greater than that of Th2 responses. Two-colour flow cytometric analysis showed that mice exposed prenatally to BPA had 29% and 100% more splenic CD3 + CD4 + and CD3 + CD8 + cells, respectively, than control animals. Similar results were obtained from females whose mothers had consumed BPA during pregnancy. These results suggest that prenatal exposure to BPA may result in the up-regulation of immune responses, especially Th1 responses, in adulthood.