Molting and metamorphosis are stimulated by the secretion of ecdysteroid hormones from the prothoracic glands. Insulin-like hormones have been found to enhance prothoracic gland activity, providing a mechanism to link molting to nutritional state. In silk moths (Bombyx mori), the prothoracic glands are directly stimulated by insulin and the insulin-like hormone bombyxin. Further, in Bombyx, the neuropeptide prothoracicotropic hormone (PTTH) appears to act at least in part through the insulin-signaling pathway. In the prothoracic glands of Manduca sexta, while insulin stimulates the phosphorylation of the insulin receptor and Akt, neither insulin nor bombyxin II stimulate ecdysone secretion. Involvement of the insulin-signaling pathway in Manduca prothoracic glands was explored using two inhibitors of phosphatidylinositol-3-kinase (PI3K), LY294002 and wortmannin. PI3K inhibitors block the phosphorylation of Akt and 4EBP but have no effect on ecdysone secretion, or on the phosphorylation of the MAPkinase, ERK. Inhibitors that block phosphorylation of ERK, including the MEK inhibitor U0126, and high doses of the RSK inhibitor SL0101, effectively inhibit ecdysone secretion. The results highlight differences between the two lepidopteran insects most commonly used to directly study ecdysteroid secretion. In Bombyx, the PTTH and insulin-signaling pathways intersect; both insulin and PTTH enhance the phosphorylation of Akt and stimulate ecdysteroid secretion, and inhibition of PI3K reduces ecdysteroid secretion. By contrast, in Manduca, the action of PTTH is distinct from insulin. The results highlight species differences in the roles of translational regulators such as 4EBP, and members of the MAPkinase pathway such as ERK and RSK, in the regulation of insect ecdysone secretion, and in the impact of nutritionally-sensitive hormones such as insulin in the control of ecdysone secretion and molting.
Advances in our ability to identify lymphatic endothelial cells and differentiate them from blood endothelial cells have led to important progress in the study of lymphatic biology. Over the past decade, preclinical and clinical studies have shown that there are changes to the lymphatic vasculature in nearly all lung diseases. Efforts to understand the contribution of lymphatics and their growth factors to disease initiation, progression, and resolution have led to seminal findings establishing critical roles for lymphatics in lung biology spanning from the first breath after birth to asthma, tuberculosis, and lung transplantation. However, in other diseases, it remains unclear if lymphatics are part of the overall lung remodeling process or real contributors to disease pathogenesis. The goal of this Translational Review is to highlight some of the advances in our understanding of the role(s) of lymphatics in lung disease and shed light on the critical needs and unanswered questions that might lead to novel translational applications.
Somatic or germline mutations in the tuberous sclerosis complex (TSC) tumor suppressor genes are associated closely with the pathogenesis of lymphangioleiomyomatosis (LAM), a rare and progressive neoplastic disease that predominantly affects women in their childbearing years. Serum levels of the lymphangiogeneic growth factor VEGF-D are elevated significantly in LAM. However, there are gaps in knowledge regarding VEGF-D dysregulation and its cellular origin in LAM. Here we show that increased expression and activation of the tyrosine kinase Syk in TSC2-deficient cells and pulmonary nodules from LAM patients contributes to tumor growth. Syk kinase inhibitors blocked Syk signaling and exhibited potent anti-proliferative activities in TSC2-deficient cells and an immunodeficient mouse xenograft model of LAM. In TSC2-deficient cells, Syk signaling increased expression of monocyte chemoattractant protein MCP-1, which in peripheral blood mononuclear cells (PBMC) stimulated production of VEGF-D. In clinical isolates of PBMC from LAM patients, VEGF-D expression was elevated. Further, levels of VEGF-D and MCP-1 in patient sera correlated positively with each other. Our results illuminate the basis for LAM growth and demonstrate the therapeutic potential of targeting Syk in this and other settings driven by TSC genetic mutation.
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