Immunology, Endocrine & Metabolic Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Immunology, Endocrine and Metabolic Agents) - Volume 9, Issue 2, 2009

Angiogenesis is regulated by a number of endogenous stimulators and inhibitors and involves multiple biological steps, including endothelial cell proliferation, cell migration, cell-cell and cell-matrix adhesion and assembly into tube structures. Designing and developing peptides or non-peptide mimetics for therapeutic application to stimulate or inhibit angiogenesis is an important current area in drug development. Information coded in endogenous protein angiogenesis stimulators and inhibitors hold is important to the design of anti-angiogenesis peptides and, ultimately, non-peptide mimetic. Several hormones affect angiogenesis via their interactions with extracellular matrix molecules, cell surface receptors and proteases, as well as growth factors and cytokines. Recent reports have ascribed pro-angiogenic activity to several thyroid hormone analogues, including Lthyroxine (T4), 3,5,3'-triiodo-L-thyronine (T3) and diiodothyropropionic acid (DITPA). Model systems of angiogenesis have demonstrated that thyroid hormone-induced neovascularization is initiated at a cell surface integrin receptor. The hormone signal is transduced within the cell by cell surface integrin-extracellular matrix regulated kinase 1/2 (ERK1/2), leading to secretion of basic fibroblast growth factor (bFGF) and other growth factors and resulting in angiogenesis. Studies in intact animal have shown that endogenous or exogenous thyroid hormone supports blood vessel density in heart, brain and ischemic limbs. Additionally, other steroid hormones and insulin-glucose homeostasis play key roles in modulating angiogenesis. This review will highlight several hormonal systems that affect angiogenesis, but will focus largely on the thyroid hormone-integrin interaction that affects neovascularization.

Thyroid hormone and estrogen have nongenomic, as well as genomic, mechanisms of action. Some of these nongenomic actions of thyroid hormone and estrogen are similar or identical. For example, transduction mechanisms of thyroid hormone and estradiol signals at discrete plasma membrane hormone-binding sites of breast cancer cells, but both then utilize activation of mitogen-actrivated protein kinase (MAPK), depend upon MAPK-requiring phosphorylation of serine-118 of the nuclear estrogen receptor (ER)-α and culminate in genomically-directed, ER-dependent breast cancer cell proliferation. In this review, several mechanisms of action of estrogen and thyroid hormone are discussed that are initiated nongenomically, but, downstream of initiation sites are similar or shared. Some of these effects end genomically. The actions include hormone-directed angiogenesis, modulation of activities of plasma membrane ion transporters, regulation of the state of the actin cytoskeleton and stimulation of cancer cell proliferation, including breast and, surprisingly, thyroid cancer.

Preventing or curing an immune-mediated disease requires functional immune cells, in particular T cells, including helper (CD4+; Th) and cytotoxic (CD8+; Tc) T cells. Based on the type of the antigen presenting cells, the nature of antigens, and the cytokine milieu, CD4+ T cells exhibit high plasticity to differentiate into different subsets with stimulatory or regulatory functions. For instance, Th cells can differentiate into Th1 and Th2 type cells, which produce inflammatory (IL-2, IFN-γ, TNF-α, IL-12) and anti-inflammatory (IL-4, IL-10, and TGF-ß) cytokines, respectively. Th cells can also differentiate into a third type of Th cells designated as Th17 type cell that produces IL-17 and mimics the effects of Th1 cells. Similar to Th cells, Tc can differentiate into Tc1, Tc2, and Tc17 subsets that produce cytokine profiles similar to those produced by Th1, Th2, and Th17 cells, respectively. Under certain condition, Th type cells can also differentiate into a regulatory (Treg) type cell, which produces immunosuppressive cytokines such as TGF-ß and IL-10. Similarly, Th17 and Tc1 type cells can acquire immunoreglatory properties. This article sheds a light on how this T cell plasticity shapes the nature of the immune cell responses to inflammation, infection, and cancer.

The host innate immune system represents the first line of defense against invasive pathogens. During the crucial early stages of infection, the host innate immune system must be able to rapidly detect and respond to foreign pathogens, enabling an efficient and successful adaptative immune response. Leishmania parasites are obligate intracellular eukaryotic pathogens living inside cells of the mononuclear phagocytic system. Recent data has proven distinct roles of various phagocytic cells, such as neutrophils, macrophages and dendritic cells during Leishmania infection. There is growing evidence that Leishmania modifies antigen presentation, apoptosis and immunoregulatory functions on these cells, leading to persistent and chronic infection. At the molecular level, the Toll-like receptors (TLR) family is a major player in the early host-pathogen interaction. The TLRs expressed intracellularly or at the surface of the cells involved in the innate immune response recognize conserved structures on foreign pathogens, such as Leishmania, playing a pivotal role in triggering innate and adaptative immune responses. Nonetheless, the same TLRs can be considered as a potential strategic target used by these organisms for their own advantage. In this review, we discussed the findings on the cellular processes involved in the innate host defense against intracellular pathogens, focusing on the Leishmania infection, from the initial host-parasite interactions involved in the parasite recognition to the mechanisms employed to eliminate the pathogen, presenting new data on the role of TLR2 in visceral leishmaniasis.