Cytokines play essential roles in innate and adaptive immunity. However, excess cytokines or dysregulation of cytokine signaling will cause a variety of diseases, including allergies, autoimmune diseases, inflammation, and cancer. Most cytokines utilize the so-called Janus kinase–signal transducers and activators of transcription pathway. This pathway is negatively regulated by various mechanisms including suppressors of cytokine signaling (SOCS) proteins. SOCS proteins bind to JAK or cytokine receptors, thereby suppressing further signaling events. Especially, suppressor of cytokine signaling-1 (SOCS1) and SOCS3 are strong inhibitors of JAKs, because these two contain kinase inhibitory region at the N-terminus. Studies using conditional knockout mice have shown that SOCS proteins are key physiological as well as pathological regulators of immune homeostasis. Recent studies have also demonstrated that SOCS1 and SOCS3 are important regulators of helper T cell differentiation and functions. This review focuses on the roles of SOCS1 and SOCS3 in T cell mediated inflammatory diseases.

How the innate and adaptive immune systems cooperate in the natural history of allergic diseases has been largely unknown. Plant-derived allergen, papain, and mite allergens, Der f 1 and Der p 1, belong to the same family of cysteine proteases. We examined the role of protease allergens in the induction of Ab production and airway inflammation after repeated intranasal administration without adjuvants and that in basophil/mast cell stimulation in vitro. Papain induced papain-specific IgE/IgG1 and lung eosinophilia. Der f 1 induced Der f 1–specific IgG1 and eosinophilia. Although papain-, Der f 1–, and Der p 1–stimulated basophils expressed allergy-inducing cytokines, including IL-4 in vitro, basophil-depleting Ab and mast cell deficiency did not suppress the papain-induced in vivo responses. Protease inhibitor–treated allergens and a catalytic site mutant did not induce the responses. These results indicate that protease activity is essential to Ab production and eosinophilia in vivo and basophil activation in vitro. IL-33–deficient mice lacked eosinophilia and had reduced papain-specific IgE/IgG1. Coadministration of OVA with papain induced OVA-specific IgE/IgG1, which was reduced in IL-33–deficient mice. We demonstrated IL-33 release, subsequent IL-33–dependent IL-5/IL-13 release, and activation of T1/ST2-expressing lineage−CD25+CD44+ innate lymphoid cells in the lung after papain inhalation, suggesting the contribution of the IL-33–type 2 innate lymphoid cell–IL-5/IL-13 axis to the papain-induced airway eosinophilia. Rag2-deficient mice, which lack adaptive immune cells, showed significant, but less severe, eosinophilia. Collectively, these results suggest cooperation of adaptive immune cells and IL-33–responsive innate cells in protease-dependent allergic airway inflammation.

Transplantation of endothelial cells (ECs) is a promising therapeutic approach for ischemic disorders. In addition, the generation of ECs has become increasingly important for providing vascular plexus to regenerated organs, such as the liver. Although many attempts have been made to generate ECs from pluripotent stem cells and nonvascular cells, the minimum number of transcription factors that specialize in directly inducing vascular ECs remains undefined. Here, by screening 18 transcription factors that are important for both endothelial and hematopoietic development, we demonstrate that ets variant 2 (ETV2) alone directly converts primary human adult skin fibroblasts into functional vascular endothelial cells (ETVECs). In coordination with endogenous FOXC2 in fibroblasts, transduced ETV2 elicits expression of multiple key endothelial development factors, including FLI1, ERG, and TAL1, and induces expression of endothelial functional molecules, including EGFL7 and von Willebrand factor. Consequently, ETVECs exhibits EC characteristics in vitro and forms mature functional vasculature in Matrigel plugs transplanted in NOD SCID mice. Furthermore, ETVECs significantly improve blood flow recovery in a hind limb ischemic model using BALB/c-nu mice. Our study indicates that the creation of ETVECs provides further understanding of human EC development induced by ETV2.uman vascular endothelial cells (ECs) generated from pluripotent stem cells (PSCs), including embryonic stem cells and induced PSCs (iPSCs), or nonvascular cells have great therapeutic potential for treating ischemic vascular diseases (1, 2). In addition, the generation of ECs has become increasingly important for providing vascular plexus to regenerated organs, such as the liver (3). iPSCs are an especially promising source for creating ECs, although the main limitation of applying iPSCs is the risk of incomplete differentiation and tumorigenicity (4, 5). To bypass the fully pluripotent state, multiple research groups have generated ECs by culturing fibroblasts transduced with iPSCinducing factors (OCT4, SOX2, KLF4, and c-MYC) under defined EC culture conditions (6, 7). The long-term stability of these ECs remains to be established, however; the PSC-derived ECs often show poor proliferative abilities and drift into nonvascular lineages (8).Combined expression of multiple transcription factors specific to a particular lineage has been demonstrated to change somatic cell fate by bypassing pluripotency; for example, Gata4, Mef2c, and Tbx5 convert murine cardiac fibroblasts into functional cardiomyocytes (9), and Ascl1, Brn2, and Myt1 induce neurons from murine fibroblasts (10). This "direct lineage conversion" approach offers promising prospects for creating cells of biomedical interest for cellular replacement therapies. This approach is also useful for studying the physiological mechanisms of transcriptional reprogramming, such as the establishment of cellular identity, and the transcriptional regulatory networks that drive terminal differentiation and fu...