Urinary heme oxygenase-1 as a potential biomarker for early diabetic nephropathy.

Background: Our previous study showed that increases of urinary heme oxygenase-1 (uHO-1) could be a potential biomarker indicating evaluating intrarenal oxidative damage in obstructive nephropathy. Activation of oxidative stress is an important mediator of diabetic nephropathy (DN). The aim of this study was to investigate the clinical implications of uHO-1 levels in patients with type 2 diabetes.

β2-Adrenergic agonists bias TLR-2 and NOD2 activated dendritic cells towards inducing an IL-17 immune response.

This study tested the hypothesis that activation of β2-adrenoceptors on DCs influences NOD2 signaling along with its cross-talk with Toll-like receptor-2 resulting in altered Th cell priming ability. Th17 cells are a newly discovered lineage of CD4(+) T cells involved in defense against extracellular bacteria and also implicated in autoimmune disorders. Initiation and polarization of the adaptive immune response is controlled by innate immune recognition mediated by DCs.

Adrenergic modulation of dendritic cell cancer vaccine in a mouse model: role of dendritic cell maturation.

The aim of the present study was to evaluate the role of beta2-adrenergic receptors (beta2-ARs) in the outcome of a dendritic cell (DC)-based cancer vaccine in the murine E.G7-ovalbumin (OVA) model. We found that unlike the beta2-AR expressed on antigen loaded DCs, beta2-ARs expressed in the site of DCs inoculation may influence the efficacy of the antitumor response.

Sympathetic nervous modulation of the skin innate and adaptive immune response to peptidoglycan but not lipopolysaccharide: involvement of beta-adrenoceptors and relevance in inflammatory diseases.

Disorders of the skin immune activity are implicated in the pathogenesis of acquired inflammatory skin disorders. Inflammatory diseases including psoriasis, atopic dermatitis, lichen planus and vitiligo have also been associated with local alterations of adrenergic mechanisms and emotional stress. Here we show that the beta-adrenergic receptors antagonist propranolol along with peptidoglycan, but not LPS, combined with intradermal injection of a soluble protein, shifted the recall memory response to the Th1 type.

Sympathetic nervous system influence on the innate immune response.

Our studies focused on the sympathetic nervous system (SNS) influence on dendritic cells (DCs), which play a crucial role in the innate immune response. We found that DCs express a variety of adrenergic receptors (ARs) with alpha1-ARs playing a stimulatory and beta2-ARs an inhibitory effect on DCs migration. beta2-ARs in skin and bone marrow-derived DCs when stimulated by bacterial toll-like receptors (TLRs) agonists respond to norepinephrine (NE) by decreased interleukin-12 (IL-12) and increased IL-10 production which in turn downregulates inflammatory cytokine production and CCR7 expression and thus their migration ability leading to reduced T helper-1 (Th1) priming.

Adrenergic modulation of dendritic cells function: relevance for the immune homeostasis.

Dendritic cells (DC) play a key role in determining the appropriate immune response to invading pathogens and tolerance to self antigens. Here I review the evidence that dendritic cell functions may be tuned by the sympathetic nervous system via the local release of norepinephrine. In the presence of antigens or microbial products, such as agonists for Toll-like receptors 2 and 4, norepinephrine inhibits dendritic cell migration, antigen presentation and T-helper cells type 1 priming.

Does melatonin play a disease-promoting role in rheumatoid arthritis?

The pineal neurohormone melatonin (MLT) has been widely shown to exert an immunostimulatory and antiapoptotic role, mainly by acting on Th cells and on T and B cell precursors, respectively. Thus, MLT might favor or promote autoimmune diseases by acting directly on immature and mature immunocompetent cells. In fact, preclinical and clinical evidence point to a disease-promoting role of MLT in rheumatoid arthritis (RA).

The endogenous cannabinoid 2-arachidonoyl glycerol as in vivo chemoattractant for dendritic cells and adjuvant for Th1 response to a soluble protein.

The decision-making mechanisms that determine the choice of the appropriate effector immune response to a microbial challenge are poorly understood. The endocannabinoid 2-arachidonoylglycerol (2-AG), injected intradermally in mice together with a soluble protein and a T helper-2 (Th2) priming Toll-like receptors (TLRs) agonist during primary immunization, shifts the memory response to the Th1 type. This effect can be shown by the enhanced hypersensitivity response and by the Th1 pattern of cytokines production that was abolished by the specific cannabinoid receptor CB2 antagonist SR 144528.

Modulation of skin norepinephrine turnover by allergen sensitization: impact on contact hypersensitivity and T helper priming.

The information gathered by dendritic cells during the innate immune response is determinant for the type and strength of the adaptive response. We showed that the sympathetic neurotransmitter norepinephrine influences dendritic cell migration and T helper priming via alpha- and beta-adrenoceptors. Others have shown that Langerhans cells also express mRNA for beta 1-, beta 2-, and alpha 1A-adrenoceptors and that catecholamines may inhibit the antigen-presenting capability via beta 2-adrenoceptors.

Langerhans cells beta 2-adrenoceptors: role in migration, cytokine production, Th priming and contact hypersensitivity.

We showed that norepinephrine (NE) hampers IL-12 and stimulates IL-10 production via adrenoceptors (ARs) in bone marrow-derived dendritic cells (BMDC) influencing their Th priming ability. Others have shown that Langerhans cells (LC) express mRNA for beta1-, beta2- and alpha1(A)-(ARs) and that catecholamines may inhibit the antigen-presenting capability via beta2-ARs. Here, we show that also BMDC express mRNA for beta1-, beta2-, alpha2(A)- and alpha2(C)-ARs.

Short exposure of maturing, bone marrow-derived dendritic cells to norepinephrine: impact on kinetics of cytokine production and Th development.

The information gathered by dendritic cells (DC) during the innate immune response to a pathogen is determinant for the type of adaptive response. Here we show that short-term (3 h) exposure of bone marrow-derived DC to norepinephrine (NE), at the beginning of lipopolysaccharide (LPS) or keyhole limpet hemocyanin (KLH) stimulation hampers IL-12 production and increases IL-10 release. The NE effect was mediated by both beta- and alpha2-adrenergic receptors.

Evidence for a neuroimmunomodulatory and a hematopoietic role of the Luschka's coccygeal body(3).

OBJECTIVES: In humans the glomus coccygeus was described in 1860 by Luschka. It is present at the coccyx tip and corresponds to a complex anastomosis between the median sacral artery and vein, and it is innervated by sympathetic fibers. In rats and mice it has been located in the tail ventral face.

Neurohormones and catecholamines as functional components of the bone marrow microenvironment.

A variety of cytokines and growth factors exert a finely tuned control on the complex series of proliferative and differentiative events called hematopoiesis. Recent studies have shown that neuroendocrine and neural factors may also regulate hematopoiesis. In particular, besides its important immunoenhancing properties, the pineal neurohormone melatonin can also rescue hematopoiesis from the toxic effect of anti-cancer drugs via the action of T-helper cell novel opioid cytokines.

The immunotherapeutic potential of melatonin.

The interaction between the brain and the immune system is essential for the adaptive response of an organism against environmental challenges. In this context, the pineal neurohormone melatonin (MEL) plays an important role. T-helper cells express G-protein coupled cell membrane MEL receptors and, perhaps, MEL nuclear receptors.

Dendritic cell migration controlled by alpha 1b-adrenergic receptors.

Dendritic cells (DC) bring Ags into lymphoid organs via lymphatic vessels. In this study, we investigated the possibility that the sympathetic neurotransmitter norepinephrine (NE) influences DC migration. Murine epidermal Langerhans cells mobilization is enhanced by systemic treatment with the alpha(2)-adrenergic antagonist yohimbine and inhibited by local treatment with the specific alpha(1)-adrenergic antagonist prazosin (PRA).

Evidence for melatonin synthesis in mouse and human bone marrow cells.

Recently, it was demonstrated that inbred strains of mice have a clearcut circadian rhythm of pineal and serum melatonin. Moreover, it is known that melatonin is involved in many immunoregulatory functions. Among them, hematopoiesis is influenced by the action of melatonin via melatonin-induced opioids on kappa-opioid receptors, which are present on stromal bone marrow cells.

MLT and the immune-hematopoietic system.

It is now well recognized that a main actor in the continuous interaction between the nervous and immune systems is the pineal hormone MLT. T-helper cells bear G-protein coupled MLT cell membrane receptors and, perhaps, MLT nuclear receptors. Activation of MLT receptors enhances the release of T-helper cell type 1 (Th1) cytokines, such as gamma-interferon and interleukin-2 (IL-2), as well as of novel opioid cytokines which crossreact immunologically with both interleukin-4 (IL-4) and dynorphin B.

Therapeutic potential of melatonin in immunodeficiency states, viral diseases, and cancer.

Maintenance of health depends on the ability to respond appropriately to environmental stressors via reciprocal interactions between the body and the brain. In this context, it is well recognized that the pineal hormone melatonin (MLT) plays an important role. T-helper cells bear G-protein-coupled MLT cell membrane receptors and, perhaps, MLT nuclear receptors.

Hematopoietic effect of melatonin involvement of type 1 kappa-opioid receptor on bone marrow macrophages and interleukin-1.

Melatonin has immuno-enhancing properties and exerts colony-stimulating activity (CSA) via T-helper cell-derived opioids. Opioid agonists may mimic the CSA of melatonin with an order of potency that suggests the presence of a type 1 kappa-opioid receptor (type 1 kappaOR [kappa]-OR]). The kappaOR antagonist nor-binaltorphimine neutralized the in vitro effect of melatonin and inhibited regeneration of hematopoiesis in mice treated with carboplatin.

Neural and endogenous catecholamines in the bone marrow. Circadian association of norepinephrine with hematopoiesis?

Members of our research team have recently reported that adrenergic agents may affect hematopoiesis via alpha1-adrenoceptors present on bone marrow B cell precursors. In this paper we demonstrate that murine bone marrow contains a substantial amount of catecholamines. Norepinephrine (NE) and dopamine (DA) exhibited a daily rhythmicity, with peak values observed during the night.

The photoperiod transducer melatonin and the immune-hematopoietic system.

The pineal neurohormone melatonin functionally synchronizes the organism with the photoperiod. It is now well recognized that melatonin also plays an important immunoregulatory role. T-helper cells bear G-protein coupled melatonin cell-membrane receptors and, perhaps, melatonin nuclear receptors.

kappa-Opioid receptors in marrow stroma mediate the hematopoietic effects of melatonin-induced opioid cytokines.

Melatonin exerts colony-stimulating activity and rescues myeloid progenitors from apoptosis, induced either in vivo or in vitro by cancer chemotherapy compounds in tumor-bearing mice. These effects are mediated mainly by T-helper cell-derived opioid cytokines with an apparent molecular mass of 15 kDa and 67 kDa that are recognized both by anti-interleukin-4 and anti-dynorphin B antibodies. These putative new cytokines were named melatonin-induced-opioid (MIO).

Norepinephrine protects mice from acute lethal doses of carboplatin.

We demonstrated in previous studies that adrenergic agents may affect hematopoiesis via high- and low-affinity alpha1-adrenoceptors present on bone marrow (BM) cells [1-3]. Here we show that norepinephrine administration in mice rescued hematopoiesis from the toxic effect of the non-cell cycle specific chemotherapeutic agent, carboplatin. Protection of granulocyte/macrophage colony-forming units (GM-CFUs) was already apparent only a few hours after carboplatin and norepinephrine administration.