A new class of inflammatory CD4؉ T cells that produce interleukin-17 (IL-17) (termed Th17) has been identified, which plays a critical role in numerous inflammatory conditions and autoimmune diseases. Interleukin-17A (IL-17A)-producing T cells are a subset of CD4 ϩ T cell lineage, termed Th17, distinct from Th1, Th2, and T regulatory (T reg ) subsets (52). IL-17 is involved in the pathogenesis of autoimmune inflammation and has been implicated in numerous autoimmune diseases, including systemic lupus erythematosus, rheumatoid arthritis, and multiple sclerosis (MS) (10,21,26,41). IL-17 mRNA and protein levels in patients with MS have been shown to be increased in mononuclear cells isolated from blood, in cerebrospinal fluid, and in brain lesions (39,41). IL-17 is also increased in lymphocytes derived from mice with experimental autoimmune encephalomyelitis (EAE; mouse model for multiple sclerosis) (33). In IL-17A knockout (KO) mice, EAE is markedly suppressed, indicating that IL-17 contributes to the development of EAE (33). Although it has been reported that the transcription factors nuclear factor for activated T cells (NFAT), retinoid orphan nuclear receptor ␥t (ROR␥t), and Runt-related transcription factor 1 (Runx1) are important for the T cell receptor (TCR)-mediated transcriptional regulation of IL-17A (24, 29, 38, 74), knowledge of the factors involved in the cellular and molecular regulation of IL-17A remains limited.The principle function of the active form of vitamin D,, is the maintenance of calcium and phosphate homeostasis (13). However, vitamin D has numerous other functions, including downregulation of autoimmunity (7,8,25,55). 1,25(OH) 2 D 3 has been reported to at least partially protect against a number of experimental autoimmune diseases, including EAE (7,8,11,35,40,53). In addition, numerous epidemiological studies have indicated a negative correlation between increased sun exposure, which would result in a higher vitamin D synthetic rate, and diets rich in vitamin D and MS prevalence (34,55,70
Summary• Soybean cyst nematodes (Heterodera glycines) produce secreted effector proteins that function as peptide mimics of plant CLAVATA3 ⁄ ESR (CLE)-like peptides probably involved in the developmental reprogramming of root cells to form specialized feeding cells called syncytia.• The site of action and mechanism of delivery of CLE effectors to host plant cells by the nematode, however, have not been established. In this study, immunologic, genetic and biochemical approaches were used to reveal the localization and site of action of H. glycines-secreted CLE proteins in planta.• We present evidence indicating that the nematode CLE propeptides are delivered to the cytoplasm of syncytial cells, but ultimately function in the apoplast, consistent with their proposed role as ligand mimics of plant CLE peptides. We determined that the nematode 12-amino-acid CLE motif peptide is not sufficient for biological activity in vivo, pointing to an important role for sequences upstream of the CLE motif in function.• Genetic and biochemical analysis confirmed the requirement of the variable domain in planta for host-specific recognition and revealed a novel role in trafficking cytoplasmically delivered CLEs to the apoplast in order to function as ligand mimics.
Vitamin D maintains calcium homeostasis and is required for bone development and maintenance. Recent evidence has indicated an interrelationship between vitamin D and health beyond bone, including effects on cell proliferation and on the immune system. New developments in our lab related to the function and regulation of target proteins have provided novel insights into the mechanisms of vitamin D action. Studies in our lab have shown that the calcium-binding protein, calbindin, which has been reported to be a facilitator of calcium diffusion, also has an important role in protecting against apoptotic cell death in different tissues including protection against cytokine destruction of osteoblastic and pancreatic beta cells. These findings have important implications for the therapeutic intervention of many disorders including diabetes and osteoporosis. Recent studies in our laboratory of intestinal calcium absorption using calbindin-D(9k) null mutant mice as well as mice lacking the 1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)) inducible epithelial calcium channel, TRPV6, provide evidence for the first time of calbindin-D(9k) and TRPV6 independent regulation of active calcium absorption. Besides calbindin, the other major target of 1,25(OH)(2)D(3) in intestine and kidney is 25(OH)D(3) 24 hydroxylase (24(OH)ase), which is involved in the catabolism of 1,25(OH)(2)D(3). In our laboratory we have identified various factors that cooperate with the vitamin D receptor in regulating 24(OH)ase expression including C/EBP beta, SWI/SNF (complexes that remodel chromatin using the energy of ATP hydrolysis) and the methyltransferases, CARM1 and G9a. Evidence is also presented for C/EBP beta as a nuclear coupling factor that coordinates regulation of osteopontin by 1,25(OH)(2)D(3) and PTH. Our findings define novel mechanisms that may be of fundamental importance in understanding how 1,25(OH)(2)D(3) mediates its multiple biological effects.
Background:The skeleton regulates glucose metabolism and energy expenditure. Results: Two transcription factors interact to regulate the activity of an osteoblast-secreted hormone favoring energy metabolism. Conclusion:The skeleton utilizes an intricate transcriptional machinery to maintain energy homeostasis. Significance: Transcription factor-mediated regulation of energy metabolism by the skeleton has potential applications in diseases of abnormal glucose metabolism.
Vitamin D is a principal regulator of calcium homeostasis. However, recent evidence has indicated that vitamin D can have numerous other physiological functions including inhibition of proliferation of a number of malignant cells including breast and prostate cancer cells and protection against certain immune mediated disorders including multiple sclerosis (MS). The geographic incidence of MS indicates an increase in MS with a decrease in sunlight exposure. Since vitamin D is produced in the skin by solar or UV irradiation and high serum levels of 25-hydroxyvitamin D (25(OH)D) have been reported to correlate with a reduced risk of MS, a protective role of vitamin D is suggested. Mechanisms whereby the active form of vitamin D, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3 ) may act to mediate this protective effect are reviewed. Due to its immunosuppressive actions, it has been suggested that 1,25(OH)2D3 may prevent the induction of MS.
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