Genomic medicine and lung diseases.

The recent explosion of genomic data and technology points to opportunities to redefine lung diseases at the molecular level; to apply integrated genomic approaches to elucidate mechanisms of lung pathophysiology; and to improve early detection, diagnosis, and treatment of lung diseases. Research is needed to translate genomic discoveries into clinical applications, such as detecting preclinical disease, predicting patient outcomes, guiding treatment choices, and most of all identifying potential therapeutic targets for lung diseases. The Division of Lung Diseases in the National Heart, Lung, and Blood Institute convened a workshop, "Genomic Medicine and Lung Diseases," to discuss the potential for integrated genomics and systems approaches to advance 21st century pulmonary medicine and to evaluate the most promising opportunities for this next phase of genomics research to yield clinical benefit.

Loss of nuclear pro-IL-16 facilitates cell cycle progression in human cutaneous T cell lymphoma.

Cutaneous T cell lymphomas (CTCLs) represent a heterogeneous group of non-Hodgkin lymphomas that affect the skin. The pathogenesis of these conditions is poorly understood. For example, the signaling mechanisms contributing to the dysregulated growth of the neoplastic T cells are not well defined.

A genome-wide association study of plasma total IgE concentrations in the Framingham Heart Study.

Background: Atopy and plasma IgE concentration are genetically complex traits, and the specific genetic risk factors that lead to IgE dysregulation and clinical atopy are an area of active investigation.

Objective: We sought to ascertain the genetic risk factors that lead to IgE dysregulation.

Methods: A genome-wide association study (GWAS) was performed in 6819 participants from the Framingham Heart Study (FHS).

Human immunodeficiency virus type 1 gp120 reprogramming of CD4+ T-cell migration provides a mechanism for lymphadenopathy.

Infection by human immunodeficiency virus type 1 (HIV-1) is associated with decreases in peripheral CD4(+) T cells and development of lymphadenopathy. The precise mechanisms by which HIV-1 induces these changes have not been elucidated. T-cell trafficking through lymphoid tissues is facilitated by CCL21-mediated entry and sphingosine-1-phosphate (S1P)-mediated egress.

Measurement of interleukin 16.

Interleukin 16 (IL-16) is a chemoattractant immunomodulatory cytokine that initiates its cellular responses through interaction with membrane-expressed CD4. The protein may be detected by a number of methods; the choice of protocol will depend on the ultimate object of a particular experiment. The first method presented is the use of ELISA to measure IL-16 in cell culture supernatants or biological fluids.

Pro-IL-16 recruits histone deacetylase 3 to the Skp2 core promoter through interaction with transcription factor GABP.

Pro-IL-16 is a PDZ domain-containing protein expressed in T cells. Our previous work showed that upon activation of normal T cells, pro-IL-16 mRNA and protein are diminished in close correlation to the down-regulation of p27KIP1 protein. In addition, we showed that pro-IL-16 regulates the transcription of Skp2, the mechanism of which, however, remains elusive.

Histamine 4 receptor activation induces recruitment of FoxP3+ T cells and inhibits allergic asthma in a murine model.

Histamine has an important role in regulation of immune response which is mediated by differential expression of four distinct receptors, H1R-H4R. H1R and HR2 have previously been shown to be involved with modulation of lung inflammation. H4R is also expressed on inflammatory cells; therefore, we investigated the potential role of H4R in development of allergic asthma in a murine model.

Chemokine receptor CXCR3 desensitization by IL-16/CD4 signaling is dependent on CCR5 and intact membrane cholesterol.

Previous work has shown that IL-16/CD4 induces desensitization of both CCR5- and CXCR4-induced migration, with no apparent effect on CCR2b or CCR3. To investigate the functional relationship between CD4 and other chemokine receptors, we determined the effects of IL-16 interaction with CD4 on CXCR3-induced migration. In this study we demonstrate that IL-16/CD4 induced receptor desensitization of CXCR3 on primary human T cells.

Association of asthma with a functional promoter polymorphism in the IL16 gene.

Background: IL-16, a multifunctional cytokine with increased expression in the airways of asthmatic subjects, inhibits allergic airway inflammation in animal models. A T-->C single nucleotide polymorphism (SNP) at the -295 position in the promoter region of the IL16 gene has been described.

Objective: We sought to examine the functional significance of this promoter SNP and its relationship to asthma.

Regulation of nuclear Prointerleukin-16 and p27(Kip1) in primary human T lymphocytes.

Prointerleukin-16 (Pro-IL-16) is an abundant, PDZ domain-containing protein expressed in the nucleus and cytoplasm of resting human T lymphocytes. We have previously shown that ectopic expression of Pro-IL-16 in Pro-IL-16-negative human Jurkat cells represses transcription of the F-box protein, Skp2, resulting in accumulation of the cyclin-dependent kinase inhibitor, p27(Kip1), and G0/G1 cell cycle arrest. The current studies demonstrate the kinetics of Pro-IL-16 and p27(Kip1) expression in activated normal human T lymphocytes.

The effect of interleukin-16 and its precursor on T lymphocyte activation and growth.

Interleukin-16 (IL-16) was the first described T lymphocyte chemoattractant. It has since been shown that IL-16 also functions as a primer of T cell proliferation, a modulator of inflammatory and immune responses, a stimulus of B cell differentiation and an inhibitor of Human immunodeficiency virus (HIV) replication. Its precursor, Prointerleukin-16 (pro-IL-16), is expressed in both the nucleus and cytoplasm of T cells.

Nuclear pro-IL-16 regulation of T cell proliferation: p27(KIP1)-dependent G0/G1 arrest mediated by inhibition of Skp2 transcription.

The precursor for IL-16 (pro-IL-16) is a nuclear and cytoplasmic PDZ domain-containing protein. In this study we have found that pro-IL-16 is absent or mutated in four T lymphoblastic leukemia cell lines examined. Ectopic expression of pro-IL-16 in pro-IL-16-negative Jurkat cells blocks cell cycle progression from G(0)/G(1) to S phase associated with elevated levels of the cyclin-dependent kinase inhibitor p27(KIP1).

Cutting edge: IL-16/CD4 preferentially induces Th1 cell migration: requirement of CCR5.

IL-16 binds to CD4 and induces a migratory response in CD4(+) T cells. Although it has been assumed that CD4 is the sole receptor and that IL-16 induces a comparable migratory response in all CD4(+) T cells, this has not been investigated. In this study, we determined that IL-16 preferentially induces a migratory response in Th1 cells.

Immunomodulatory cytokines in asthmatic inflammation.

The development of asthmatic inflammation involves a complex array of cytokines that promote the recruitment and activation of a number of different immune cells. While factors involved in initiating and establishing inflammation are well characterized, the process by which this pro-inflammatory cascade is regulated is less well understood. The identification and characterization of immunomodulatory cytokines in asthma has been a difficult proposition.

Binding of HTLV-1 tax oncoprotein to the precursor of interleukin-16, a T cell PDZ domain-containing protein.

HTLV-1 Tax oncoprotein interacts with various cellular factors and modulates transcription and the cell cycle. In that role it is sufficient to create T cell malignancies in the absence of HTLV-1 infection. HTLV-1 Tax protein has been reported to bind to cellular proteins containing PDZ domains in vitro.

Tumor necrosis factor-alpha-induced synthesis of interleukin-16 in airway epithelial cells: priming for serotonin stimulation.

Epithelial cells from individuals with asthma or from allergen-sensitized mice contain intracellular interleukin (IL)-16 protein, not present in epithelial cells from individuals without asthma or unsensitized mice. IL-16 is only present in the bronchoalveolar lavage (BAL) fluid following airway challenge with either allergen or vasoactive amine. This suggests that the initial response to allergen (sensitization) results in synthesis but not secretion of IL-16.

Differential roles of IL-16 and CD28/B7 costimulation in the generation of T-lymphocyte chemotactic activity in the bronchial mucosa of mild and moderate asthmatic individuals.

Background: IL-16 is an important T-cell chemotactic cytokine in asthmatic airways; its release from allergen-stimulated bronchial mucosa in mild asthma has been shown to be dependent on CD28/B7 costimulation.

Objective: We have extended our previous studies to investigate the role of IL-16 and CD28/B7 costimulation in T-lymphocyte chemotactic activity (TLCA) released from the bronchial mucosa in more severe asthma.

Methods: TLCA was determined in the supernatants of induced sputum and allergen-stimulated bronchial mucosal explants from healthy volunteers and volunteers with mild and moderately severe asthma by means of a Boyden chamber technique.

Prointerleukin-16 contains a functional CcN motif that regulates nuclear localization.

The immunomodulatory cytokine interleukin-16 (IL-16) represents the secreted C-terminus of a larger precursor, pro-IL-16. Following cleavage by caspase 3, the residual N-terminal domain translocates into the nucleus, inducing G(0)/G(1) cell cycle arrest. We have previously identified a classical bipartite nuclear localization sequence (NLS) in the N-terminal domain of pro-IL-16.