Peripheral corticotropin-releasing hormone and urocortin in the control of the immune response

doi:10.1016/S0196-9781(01)00395-3

Peptides

Volume 22, Issue 5, May 2001, Pages 809-820

https://doi.org/10.1016/S0196-9781(01)00395-3 Get rights and content

Abstract

Immunological and cellular stress signals trigger the release of corticotropin-releasing hormone (CRH) from the spleen, thymus and inflamed tissue. In vivo and in vitro studies generally suggest that peripheral, immune CRH has pro-inflammatory effects and acts in a paracrine manner by binding to CRH-R1 and CRH-R2 receptors on neighboring immune cells. However, it now seems likely that some of the suggested pro-inflammatory actions of CRH may be attributed to novel CRH-like peptides or to the related peptide, urocortin, which is also present in immune cells and has especially high affinity for CRH-R2 receptors.

Introduction

As more sensitive techniques are being developed for the detection of peptides in plasma and tissue extracts, it is becoming increasingly clear that peptide hormones which were once believed to be solely of brain and pituitary origin are, in fact, involved in a large number of paracrine and autocrine actions with-in the periphery.

The hypothalamic peptide, corticotropin-releasing hormone (CRH), is responsible for triggering the secretion of adrenocorticotropic hormone (ACTH) from the anterior pituitary gland during times of neurological stress [57], [82], [120] and is a classical example of a neuropeptide with multiple actions in almost every tissue of the body. After the initial characterization of CRH as an ACTH releasing peptide using perfused rat pituitary cell columns and its subsequent purification from ovine [120] and rat [83] hypothalami, basic radioimmunoassays were developed to detect CRH in a variety of tissues. Gel filtration, affinity and high performance liquid chromatographic techniques were used to confirm that immunoreactive (ir) CRH from peripheral tissues had similar elution patterns to both synthetic and purified hypothalamic CRH. As with many hypothalamic peptides, CRH-like ir was found to be present in large quantities in extracted human placenta [93], which explained the increasing concentrations of ir-CRH in the circulation during the progression of pregnancy [18], [87], [88]. CRH levels appeared much lower in other tissues, yet were significant in the spinal cord, lung, pancreas, gastrointestinal tract, and adrenal glands [74], [108]. The development of a specific CRH immunoradiometric assay [56], together with immunohistochemistry, in situ hybridization, northern blot and PCR techniques, confirmed the above findings, but also led to further discoveries regarding the extensive distribution of CRH.

Section snippets

Distribution of CRH in the immune system

CRH-like ir and mRNA were first detected in cells of the immune system in 1990 using in situ hybridization histochemistry, northern blot analysis and CRH radioimmunoassay (RIA) [107]. Separation of large numbers of lymphocytes by density gradient centrifugation and neutrophils by dextran sedimentation of the lymphocyte depleted blood, followed by peptide and mRNA analysis, led to the conclusion that CRH-ir and mRNA were present in both human peripheral blood lymphocytes and neutrophils, yet in

Upregulation of CRH expression in immune cells and tissues

In experiments where adjuvant-induced arthritic rats were used as models for chronic inflammatory stress, Jessop et al. demonstrated a slight increase in CRH-ir in the spleen and thymus 14 and 11 days respectively after initiation of the inflammatory response [41]. This work provided preliminary evidence for a link between inflammation and CRH release, yet the factor responsible for initiating this release was unknown. The production of cytokines such as IL-1, IL-6 and TNF-α by activated cells

Urocortin—the new ’immune’ CRH?

In 1995 a new mammalian member of the CRH family of genes was cloned from rat midbrain [124]. Translation of the DNA sequence revealed the peptide to share 44% amino acid homology with human and rat CRH, but interestingly, it had an even greater degree of identity with fish urotensin, a brain and spinal cord peptide possessing potent ACTH releasing activity [37], [53]. Like urotensin, urocortin was found to possess high affinity for the CRH binding protein [8] (found in the brain and

CRH receptors in the immune system

Experiments which revealed binding of [¹²⁵I] CRH to spleen cells [28], peripheral sympathetic nerves [119], aortic endothelium [27] and monocytes and T-lymphocytes [96] provided the basis for further studies on the distribution and roles of CRH receptors in the immune system. Other groups later confirmed the presence of CRH binding sites in the spleen [125], and on monocytes [4], [98] and T-lymphocytes [4] demonstrating a functional coupling of these receptors to a G-protein and cAMP signaling

Effects of CRH and UCN on the immune system

There are several problems associated with observing the effects of peripherally administered CRH and UCN. Firstly, if the experiments are carried out in man, there may be some sequestering of peptide activity by the circulating CRH-binding protein [8], [76], however, if sufficient doses are given, ACTH releasing activity is observed, demonstrating that the unbound fraction of CRH or UCN in the blood does have the ability to reach its target tissues [90]. Even in experiments carried out in rats

Discussion

It seems likely that peripheral secretions of CRH and UCN are involved in the modulation of the peripheral immune response by acting at specific receptors on multiple populations of immunocytes to produce a wide range of effects (Fig. 1). The peptides are likely to be both of neural and immune cell origin, but do not appear to be released at particularly high concentrations. Different doses of peripherally administered CRH and UCN result in either an enhanced or reduced immune response, the

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Corticotropin-releasing hormone and inflammation
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The immune/inflammatory (I/I) response is characterized by the accumulation of fluid and leukocytes in extravascular tissues and is considered to protect the organism from both the initial cause of cell injury and its consequences. Activation of the innate immune system is the first step of the I/I response. It is under the influence of brain function which exerts its regulation via the peripheral nervous and endocrine systems. Hypothalamic-pituitary-adrenal (HPA) axis is one of these systems and it is activated in response to stressors. Glucocorticoids and catecholamines play a major role on the balance between pro- and antiinflammatory actions. Hypothalamic corticotropin-releasing hormone (CRH) is considered to be an indirect antiinflammatory agent, via the final adrenal production of cortisol, known for its antiinflammatory actions. Alternatively, products of the I/I response influence the brain function. Immune cells produce CRH and corticotropin (ACTH) which act locally during both the early and late stages of the I/I process. This “immune” CRH and its receptors participate in the regulation of inflammatory phenomena suggesting that administration of CRH antagonists/inhibitors might improve the clinical profile of such conditions. Furthermore, this locally produced CRH (peripheral CRH) has been implicated in other physiological functions, such as reproduction. Together with its receptors, it has been identified in most female reproductive tissues (ovary, uterus, and placenta). Most of the CRH effects in the reproductive tract seem to be carried out via its pro-inflammatory properties as in the case of ovulation, luteolysis, and blastocyst implantation. Placental CRH concentrations increase as pregnancy progresses and it may participate in the physiology of pregnancy and the onset of parturition. Αntalarmin, a CRH antagonist, has been synthesized as a therapeutic tool for both CNS and inflammatory disorders associated with central and peripheral CRH hypersecretion. Astressin B, another CRH antagonist, accelerates the return to normal cyclicity, placing it in a very important position in the research of a potential therapeutic agent in stress-related reproductive pathology.
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Citation Excerpt :
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Our results showed an expected increase of the pro-inflammatory and anti-inflammatory response after inactivated V. anguillarum bacterin treatment in both species. Cortisol, ACTH and adrenaline did not modulate the expression of immune-related genes in rainbow trout, while in sea bream cortisol was able to reduce the stimulated gene expression of all cytokines. This effect was only restored to basal expression level in IL-1β and TNF-α by mifepristone. ACTH reduced both pro-inflammatory and anti-inflammatory cytokine expression, excluding IL-1β, only in sea bream. Adrenaline enhanced the expression of IL-1β and TGF-β1 stimulated by inactivated V. anguillarum in sea bream, and the effect was diminished by propranolol. In sum, our results confirm that the immunoendocrine differences reported at gene expression profile between two teleost species are also observed after exposure to inactivated V. anguillarum bacterin, suggesting that stress hormones would differentially modulate the immune response against pathogens in teleost species.
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Evaluar mediante ecografía el efecto del condroitín sulfato (CS) en la sinovitis de pacientes con artrosis (OA) de rodilla, y colaborar en el conocimiento de los mecanismos bioquímicos involucrados en la inflamación sinovial.
Estudio controlado, aleatorizado, ciego simple de 70 pacientes con OA de rodilla tratados durante 6 meses con CS o paracetamol (PCT). Los pacientes fueron visitados a tiempo basal, a las 6 semanas, y a los 3 y 6 meses para valorar el estado de su OA según los siguientes parámetros: sinovitis evaluada mediante ecografía (según definición de expertos OMERACT); dolor y función, mediante la escala visual analógica y el índice de Lequesne; y concentración de mediadores inflamatorios en suero y líquido sinovial, mediante ELISA.
El tratamiento con CS redujo en un 50% el número de individuos que presentaban sinovitis; sin embargo, se observó un incremento de un 123% en el grupo tratado con PCT. En los pacientes sin sinovitis inicial, se observó el establecimiento de esta en un 85,71 y 25% de los casos tratados con PCT y CS, respectivamente. Ambas terapias mejoraron la función articular, pero únicamente el tratamiento con CS produjo una mejora significativa del dolor al final del tratamiento. Se observó una asociación entre el tratamiento con CS y los cambios en la concentración de RANTES y UCN en el líquido sinovial.
El tratamiento con CS tiene un efecto mantenido beneficioso, previniendo la aparición de sinovitis o disminuyendo su presencia, así como reduciendo los síntomas de la artrosis. El PCT también mejora los síntomas clínicos, pero no tiene ningún efecto sobre la inflamación. Las variaciones observadas en la concentración de RANTES y UCN podrían estar relacionadas con el efecto antiinflamatorio asociado al tratamiento con CS.
To evaluate by ultrasonography the effect of chondroitin sulfate (CS) on synovitis in patients with knee osteoarthritis (KOA). To collaborate in the understanding of the biochemical mechanisms involved in the synovial inflammation process.
Randomized, single-blind, controlled trial involving 70 patients with primary KOA treated for 6 months with CS or acetaminophen (ACT). Evaluation of KOA status at baseline, 6 weeks, 3 and 6 months included: ultrasonography to assess synovitis (following the OMERACT expertise group definition), visual analogue scale and Lequesne index to measure pain and function, and ELISA to quantify inflammatory mediators in serum and synovial fluid.
Synovitis presence was reduced by 50% in the CS group while a 123% increase was observed in ACT group. Conversely, patients without initial synovitis and treated with ACT reached 85.71% synovitis onset, but only 25% in CS group. Both therapies improved articular function, but only CS resulted in significant pain improvement at the end of the treatment. Changes in RANTES and UCN synovial fluid concentration were associated with CS treatment.
Treatment with CS had a sustained beneficial effect, preventing synovitis onset or reducing its presence as well as reducing KOA symptoms. ACT ameliorated clinical symptoms but had no effect on inflammation. The CS anti-inflammatory effect could be related to the observed changes in RANTES and UCN concentration.
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Phagocytosis plays essential roles during inflammation and immune response. This study aims to explore the underlying mechanism of corticotropin-releasing hormone (CRH) and urocortin (UCN)-promoted phagocytosis of rat macrophages.
To induce phagocytosis, rat macrophages were incubated with carboxylated fluorescent microspheres. The phagocytosis activity was evaluated by flow cytometric analysis. Actin reorganization was determined by immunostaining with TRITC-labeled phalloidin and transmission electron microscopy (TEM) analysis. Protein expressions of p-RhoA, p-Rac1, p-extracellular signal-related kinase (ERK)1/2 and GAPDH were examined by Western blotting. Protein kinase C (PKC) and protein kinase A (PKA) activities were examined using PreTag non-radio activity assay.
Administration of CRH or UCN alone significantly enhanced phagocytosis of microspheres by rat macrophages, as well as actin reorganization. Ligation of CRH and UCN with CRH receptor increased the phosphorylation of both RhoA and Rac1. Inhibition of RhoA/Rac1 signal pathway suppressed CRH- or UCN-enhanced phagocytosis and actin reorganization. Blockage of PKA signal by MDL-12330A decreased CRH or UCN-promoted p-RhoA and p-Rac1 expressions. Blockage of PKC signal by cholerythine choride decreased CRH or UCN-promoted p-Rac1 expression and UCN-promoted p-RhoA expression, but increased the CRH-induced p-RhoA expression. ERK1/2 was also activated and served as upstream factor of RhoA/Rac1 signal pathway.
The results reveal that CRH and UCN promote phagocytosis of rat macrophages through convergent but dissociable pathways. PKA/PKC–ERK1/2-RhoA/Rac1 signal pathway plays an essential role in CRH- and UCN-enhanced phagocytosis.

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Peripheral corticotropin-releasing hormone and urocortin in the control of the immune response

Abstract

Introduction

Section snippets

Distribution of CRH in the immune system

Upregulation of CRH expression in immune cells and tissues

Urocortin—the new ’immune’ CRH?

CRH receptors in the immune system

Effects of CRH and UCN on the immune system

Discussion

Life Sci

Cell Immunol

Brain Behav Immun

J Neuroimmunol

Mol Brain Res

Neuron

Eur J Pharmacol

Eur J Pharmacol

J Neuroimmunol

J Steroid Biochem

Eur J Pharmacol

Peptides

J Neuroimmunol

J Neuroimmunol

J Neuroimmunol

Biochem Biophys Res Comm

Reg Peptides

Brain Res

Eur J Pharmacol

Biochem Biophys Res Commun

J Biol Chem

Life Sci

Neuropeptides

Neuroscience

Reg Peptides

Clin Innunol Immunopath

Pharmacol Res

J Neuroimmunol

Immunol Lett

Neurosci Lett

Immunol Lett

Peptides

Corticotropin-releasing factor mRNA in rat thymus and spleen

Proc Natl Acad Sci USA

Peripheral corticotropin-releasing factor mediates the elevation of plasma IL-6 by immobilization stress in rats

Am J Physiol

Urocortin is the principal ligand for the corticotropin-releasing hormone binding protein in the ovine brain with no evidence for a sauvagine-like peptide

J Mol Endo

mRNA expression profiles for corticotropin-releasing factor (CRH) urocortin CRH receptors and CRH-binding protein in peripheral rat tissues

J Mol Endo

Human lymphocytes produce urocortin but not corticotropin-releasing hormone

J Clin Endocrinol Metab

Isolation of the human plasma corticotrophin-releasing factor-binding protein

J Endocrinol

Corticotropin-releasing factor producing neurons in the rat activated by interleukin-1

Science

Release of multiple hormones by a direct action of interleukin-1 on pituitary cells

Science

Immunoregulatory feedback between interleukin-1 and glucocorticoid hormones

Science

Expression of corticotropin-releasing factor in the peripheral nervous system of the rat

NeuroReport

Glucocorticoids regulate proopiomelanocortin gene expression in vivo at the levels of transcription and secretion

Proc Natl Acad Sci USA

Leukocytic pyrogena major mediator of the acute phase reaction

Ann N Y Acad Sci

Interleukin-1 and interleukin-2 enhance pro-opiomelanocortin gene expression in pituitary cells

J Immunol

Plasma corticotropin-releasing hormone concentrations during pregnancy and parturition

J Clin Endocrinol Metab

Design and synthesis of a series of non-peptide high-affinity human corticotropin-releasing factor 1 receptor antagonists

J Med Chem

Expression cloning of a human corticotropin-releasing-factor receptor

Proc Natl Acad Sci USA

Local secretion of corticotropin-releasing hormone in the joints of Lewis rats with inflammatory arthritis

J Clin Invest