Luteolin Is More Potent than Cromolyn in Their Ability to Inhibit Mediator Release from Cultured Human Mast Cells.

INTRODUCTION: Mast cells are known for their involvement in allergic reactions but also in inflammatory reactions via secretion of numerous pro-inflammatory chemokines, cytokines, and enzymes. Drug development has focused on antiproliferative therapy for systemic mastocytosis and not on inhibitors of mast cell activation. The only drug available as a "mast cell blocker" is disodium cromoglycate (cromolyn), but it is poorly absorbed after oral administration, is a weak inhibitor of histamine release from human mast cells, and it develops rapid anaphylaxis. Instead, certain natural flavonoids, especially luteolin, can inhibit mast cell activation. METHODS: Here, we compared pretreatment (0-120 min) with equimolar concentration (effective dose for 50% inhibition = 100 mm for inhibition of histamine release by cromolyn) of cromolyn and luteolin on release of mediators from the cultured human LADR mast cell line stimulated either by immunoglobulin E (IgE) and anti-IgE or with IL-33. RESULTS: We show that luteolin is significantly more potent than cromolyn inhibiting release of histamine, tryptase, metalloproteinase-9, and vascular endothelial growth factor. Moreover, while luteolin also significantly inhibited release of IL-1ß, IL-6, and IL-8 (CXCL8) and TNF, cromolyn had no effect. CONCLUSION: These findings support the use of luteolin, especially in liposomal form to increase oral absorption, may be a useful alternative to cromolyn.

IL-38 inhibits microglial inflammatory mediators and is decreased in amygdala of children with autism spectrum disorder.

Autism spectrum disorder (ASD) is characterized by impaired social interactions and communication. The pathogenesis of ASD is not known, but it involves activation of microglia. We had shown that the peptide neurotensin (NT) is increased in the serum of children with ASD and stimulates cultured adult human microglia to secrete the proinflammatory molecules IL-1ß and CXCL8. This process is inhibited by the cytokine IL-37. Another cytokine, IL-38, has been reported to have antiinflammatory actions. In this report, we show that pretreatment of cultured adult human microglia with recombinant IL-38 (aa3-152, 1-100 ng/mL) inhibits (P < 0.0001) NT-stimulated (10 nM) secretion of IL-1ß (at 1 ng/mL) and CXCL8 (at 100 ng/mL). In fact, IL-38 (aa3-152, 1 ng/mL) is more potent than IL-37 (100 ng/mL). Here, we report that pretreatment with IL-38 (100 ng/mL) of embryonic microglia (HMC3), in which secretion of IL-1ß was undetectable, inhibits secretion of CXCL8 (P = 0.004). Gene expression of IL-38 and its receptor IL-36R are decreased (P = 0.001 and P = 0.04, respectively) in amygdala from patients with ASD (n = 8) compared to non-ASD controls (n = 8), obtained from the University of Maryland NeuroBioBank. IL-38 is increased (P = 0.03) in the serum of children with ASD. These findings indicate an important role for IL-38 in the inhibition of activation of human microglia, thus supporting its development as a treatment approach for ASD.

Recombinant SARS-CoV-2 Spike Protein Stimulates Secretion of Chymase, Tryptase, and IL-1ß from Human Mast Cells, Augmented by IL-33.

SARS-CoV-2 infects cells via its spike (S) protein binding to its surface receptor angiotensin-converting enzyme 2 (ACE2) and results in the production of multiple proinflammatory cytokines, especially in the lungs, leading to what is known as COVID-19. However, the cell source and the mechanism of secretion of such cytokines have not been adequately characterized. In this study, we used human cultured mast cells that are plentiful in the lungs and showed that recombinant SARS-CoV-2 full-length S protein (1-10 ng/mL), but not its receptor-binding domain (RBD), stimulates the secretion of the proinflammatory cytokine interleukin-1ß (IL-1ß) as well as the proteolytic enzymes chymase and tryptase. The secretion of IL-1ß, chymase, and tryptase is augmented by the co-administration of interleukin-33 (IL-33) (30 ng/mL). This effect is mediated via toll-like receptor 4 (TLR4) for IL-1ß and via ACE2 for chymase and tryptase. These results provide evidence that the SARS-CoV-2 S protein contributes to inflammation by stimulating mast cells through different receptors and could lead to new targeted treatment approaches.

Amyloid Beta Peptides Lead to Mast Cell Activation in a Novel 3D Hydrogel Model.

Alzheimer's disease (AD) is a prevalent neurodegenerative disease and the world's primary cause of dementia among the elderly population. The aggregation of toxic amyloid-beta (Aß) is one of the main pathological hallmarks of the AD brain. Recently, neuroinflammation has been recognized as one of the major features of AD, which involves a network of interactions between immune cells. The mast cell (MC) is an innate immune cell type known to serve as a first responder to pathological changes and crosstalk with microglia and neurons. Although an increased number of mast cells were found near the sites of Aß deposition, how mast cells are activated in AD is not clear. We developed a 3D culture system to culture MCs and investigated the activation of MCs by Aß peptides. Because collagen I is the major component of extracellular matrix (ECM) in the brain, we encapsulated human LADR MCs in gels formed by collagen I. We found that 3D-cultured MCs survived and proliferated at the same level as MCs in suspension. Additionally, they can be induced to secrete inflammatory cytokines as well as MC proteases tryptase and chymase by typical MC activators interleukin 33 (IL-33) and IgE/anti-IgE. Culturing with peptides Aß1-42, Aß1-40, and Aß25-35 caused MCs to secrete inflammatory mediators, with Aß1-42 inducing the maximum level of activation. These data indicate that MCs respond to amyloid deposition to elicit inflammatory responses and demonstrate the validity of collagen gel as a model system to investigate MCs in a 3D environment to understand neuroinflammation in AD.

Exosome-associated mitochondrial DNA from patients with myalgic encephalomyelitis/chronic fatigue syndrome stimulates human microglia to release IL-1ß.

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating disease that presents with fatigue, sleep disturbances, malaise, and cognitive problems. The pathogenesis of ME/CFS is presently unknown, and serum levels of potential biomarkers have been inconsistent. Here, we show that mitochondrial DNA (mtDNA) associated with serum exosomes, is increased in ME/CFS patients only after exercise. Moreover, exosomes isolated from patients with ME/CFS stimulate significant release of IL-1ß from cultured human microglia. These results provide evidence that activation of microglia by serum-derived exosomes may serve as a potential novel pathogenetic factor and target for treatment of ME/CFS.

IL-37 is increased in brains of children with autism spectrum disorder and inhibits human microglia stimulated by neurotensin.

Autism spectrum disorder (ASD) does not have a distinct pathogenesis or effective treatment. Increasing evidence supports the presence of immune dysfunction and inflammation in the brains of children with ASD. In this report, we present data that gene expression of the antiinflammatory cytokine IL-37, as well as of the proinflammatory cytokines IL-18 and TNF, is increased in the amygdala and dorsolateral prefrontal cortex of children with ASD as compared to non-ASD controls. Gene expression of IL-18R, which is a receptor for both IL-18 and IL-37, is also increased in the same brain areas of children with ASD. Interestingly, gene expression of the NTR3/sortilin receptor is reduced in the amygdala and dorsolateral prefrontal cortex. Pretreatment of cultured human microglia from normal adult brains with human recombinant IL-37 (1 to 100 ng/mL) inhibits neurotensin (NT)-stimulated secretion and gene expression of IL-1ß and CXCL8. Another key finding is that NT, as well as the proinflammatory cytokines IL-1ß and TNF increase IL-37 gene expression in cultured human microglia. The data presented here highlight the connection between inflammation and ASD, supporting the development of IL-37 as a potential therapeutic agent of ASD.

IL-1B(3954) polymorphism and red complex bacteria increase IL-1ß (GCF) levels in periodontitis.

OBJECTIVE: The aim of this study was to compare IL-1ß levels in gingival crevicular fluid (GCF) from healthy and periodontitis sites of IL-1B(3954)-Single Nucleotide Polymorphism (SNP) positive and IL-1B(3954)-SNP negative periodontitis subjects in association with their bacterial profiles. BACKGROUND: Susceptibility to periodontitis has been associated with several risk factors, including allelic variants at multiple gene loci. Variations in the IL-1 gene cluster have been linked with increased risk for periodontitis. IL-1B(3954)-SNP has been previously associated with increased levels of IL-1ß in GCF or periodontal tissues in chronic periodontitis patients, as well as higher levels of specific periodontal pathogens. There is insufficient evidence to conclude if IL-1B gene polymorphisms affect the susceptibility to periodontitis by ultimately modulating the levels of IL-1ß in GCF, the subgingival microbial profile or both. MATERIALS AND METHODS: GCF, subgingival plaque, and buccal epithelial cells were collected from 32 individuals with periodontitis. GCF IL-1ß levels were measured by an enzyme-linked immunosorbent assay (ELISA). Bacterial plaque samples were analyzed for 11 periodontal pathogens using polymerase chain reaction (PCR) analysis with specific primers for the 16SrRNA gene of each bacterium. IL-1B(3954)-SNP status was determined by identifying the carriers of the polymorphic T allele. RESULTS: A significant association was shown between IL-1B(3954)-SNP and IL-1ß GCF levels (amount and concentration). The concomitant presence of two or three red complex bacterial species was associated with increased IL-1ß GCF levels in periodontitis sites (site-level analysis). The concurrent presence of all three red complex periodontal pathogens and IL-1B(3954)-SNP was associated with the highest IL-1ß GCF levels in periodontitis sites. CONCLUSIONS: Our results indicate an independent association of both IL-1B(3954)-SNP and red complex bacterial species with increased IL-1ß levels in GCF of periodontitis sites. A better understanding of the interaction between genetics, bacteria, and inflammation is essential to develop more effective diagnostic, prognostic, and therapeutic tools for periodontitis.

Substance P and IL-33 administered together stimulate a marked secretion of IL-1ß from human mast cells, inhibited by methoxyluteolin.

Mast cells are critical for allergic and inflammatory responses in which the peptide substance P (SP) and the cytokine IL-33 are involved. SP (0.01-1 µM) administered together with IL-33 (30 ng/mL) to human cultured LAD2 mast cells stimulates a marked increase (P < 0.0001) in secretion of the proinflammatory cytokine IL-1ß. Preincubation of LAD2 (30 min) with the SP receptor (NK-1) antagonists L-733,060 (10 µM) or CP-96345 (10 µM) inhibits (P < 0.001) secretion of IL-1ß stimulated by either SP (1 µM) or SP together with IL-33 (30 ng/mL). Surprisingly, secretion of IL-1ß stimulated by IL-33 is inhibited (P < 0.001) by each NK-1 antagonist. Preincubation with an antibody against the IL-33 receptor ST2 inhibits (P < 0.0001) secretion of IL-1ß stimulated either by IL-33 or together with SP. The combination of SP (1 µM) with IL-33 (30 ng/mL) increases IL-1ß gene expression by 90-fold in LAD2 cells and by 200-fold in primary cultured mast cells from human umbilical cord blood. The combination of SP and IL-33 increases intracellular levels of IL-1ß in LAD2 by 100-fold and gene expression of IL-1ß and procaspase-1 by fivefold and pro-IL-1ß by twofold. Active caspase-1 is present even in unstimulated cells and is detected extracellularly. Preincubation of LAD2 cells with the natural flavonoid methoxyluteolin (1-100 mM) inhibits (P < 0.0001) secretion and gene expression of IL-1ß, procaspase-1, and pro-IL-1ß. Mast cell secretion of IL-1ß in response to SP and IL-33 reveals targets for the development of antiinflammatory therapies.

Mitochondrial dysfunction in affected skin and increased mitochondrial DNA in serum from patients with psoriasis.

Psoriasis is characterized by keratinocyte proliferation and chronic inflammation, but the pathogenesis is still unclear. Dysregulated mitochondria (mt) could lead to reduced apoptosis and extracellular secretion of mtDNA, acting as "innate pathogen" triggering inflammation. Serum was obtained from healthy volunteers and psoriatic patients. Mitochondrial DNA was extracted from the serum and amplified with quantitative PCR (qPCR). Punch biopsies were obtained from lesional and non-lesional psoriatic skin (10 cm apart) and from healthy volunteers, were placed in RNA later and were stored at -80°C until RNA was extracted and cDNA was synthesized; gene expression of uncoupling protein 2 (UCP2), Dynamin-related protein 1 (Drp1) and calcineurin, involved in the regulation of mitochondria function, was detected with qPCR. Mitochondrial DNA was significantly increased (7s, P = 0.0496 and Cytochrome B, CytB, P = 0.0403) in the serum of psoriatic patients (n = 63) as compared to controls (n = 27). Gene expression was significantly reduced for UCP2 (P = 0.0218), Drp1 (P = 0.0001) and calcineurin (P = 0.0001) in lesional psoriatic skin, as compared to non-lesional or control skin. Increased serum extracellular mtDNA in psoriatic patients and decreased expression of mitochondrial regulatory proteins in psoriatic skin suggest increased inflammation and reduced keratinocyte apoptosis, respectively. Inhibitors of mtDNA secretion and/or UCP2 stimulants may be potential treatment options.

Neurotensin stimulates sortilin and mTOR in human microglia inhibitable by methoxyluteolin, a potential therapeutic target for autism.

We had reported elevated serum levels of the peptide neurotensin (NT) in children with autism spectrum disorders (ASD). Here, we show that NT stimulates primary human microglia, the resident immune cells of the brain, and the immortalized cell line of human microglia-SV40. NT (10 nM) increases the gene expression and release (P < 0.001) of the proinflammatory cytokine IL-1ß and chemokine (C-X-C motif) ligand 8 (CXCL8), chemokine (C-C motif) ligand 2 (CCL2), and CCL5 from human microglia. NT also stimulates proliferation (P < 0.05) of microglia-SV40. Microglia express only the receptor 3 (NTR3)/sortilin and not the NTR1 or NTR2. The use of siRNA to target sortilin reduces (P < 0.001) the NT-stimulated cytokine and chemokine gene expression and release from human microglia. Stimulation with NT (10 nM) increases the gene expression of sortilin (P < 0.0001) and causes the receptor to be translocated from the cytoplasm to the cell surface, and to be secreted extracellularly. Our findings also show increased levels of sortilin (P < 0.0001) in the serum from children with ASD (n = 36), compared with healthy controls (n = 20). NT stimulation of microglia-SV40 causes activation of the mammalian target of rapamycin (mTOR) signaling kinase, as shown by phosphorylation of its substrates and inhibition of these responses by drugs that prevent mTOR activation. NT-stimulated responses are inhibited by the flavonoid methoxyluteolin (0.1-1 µM). The data provide a link between sortilin and the pathological findings of microglia and inflammation of the brain in ASD. Thus, inhibition of this pathway using methoxyluteolin could provide an effective treatment of ASD.

Mast Cells May Regulate The Anti-Inflammatory Activity of IL-37.

Mast cells are unique immune cells involved in allergic reactions, but also in immunity and inflammation. Interleukin 37 (IL-37) has emerged as an important regulatory cytokine with ability to inhibit immune and inflammatory processes. IL-37 is made primarily by macrophages upon activation of toll-like receptors (TLR) leading to generation of mature IL-37 via the action of caspase 1. In this review, we advance the premise that mast cells could regulate the anti-inflammatory activity of the IL-37 via their secretion of heparin and tryptase. Extracellular IL-37 could either dimerize in the presence of heparin and lose biological activity, or be acted upon by proteases that can generate even more biologically active IL-37 forms. Molecules that could selectively inhibit the secretion of mast cell mediators may, therefore, be used together with IL-37 as novel therapeutic agents.

Mast Cells, Stress, Fear and Autism Spectrum Disorder.

Autism Spectrum Disorder (ASD) is a developmental condition characterized by impaired communication and obsessive behavior that affects 1 in 59 children. ASD is expected to affect 1 in about 40 children by 2020, but there is still no distinct pathogenesis or effective treatments. Prenatal stress has been associated with higher risk of developing ASD in the offspring. Moreover, children with ASD cannot handle anxiety and respond disproportionately even to otherwise benign triggers. Stress and environmental stimuli trigger the unique immune cells, mast cells, which could then trigger microglia leading to abnormal synaptic pruning and dysfunctional neuronal connectivity. This process could alter the "fear threshold" in the amygdala and lead to an exaggerated "fight-or-flight" reaction. The combination of corticotropin-releasing hormone (CRH), secreted under stress, together with environmental stimuli could be major contributors to the pathogenesis of ASD. Recognizing these associations and preventing stimulation of mast cells and/or microglia could greatly benefit ASD patients.

Extracellular vesicles are increased in the serum of children with autism spectrum disorder, contain mitochondrial DNA, and stimulate human microglia to secrete IL-1ß.

BACKGROUND: Autism spectrum disorder (ASD) has been associated with brain inflammation as indicated by the activation of microglia, but the triggers are not known. Extracellular vesicles (EVs) are secreted from many cells in the blood and other biological fluids and carry molecules that could influence the function of target cells. EVs have been recently implicated in several diseases, but their presence or function in ASD has not been studied. METHODS: EVs were isolated from the serum of children with ASD (n = 20, 16 males and 4 females, 4-12 years old) and unrelated age and sex-matched normotypic controls (n = 8, 6 males and 2 females, 4-12 years old) using the exoEasy Qiagen kit. EVs were characterized by determining the CD9 and CD81 membrane-associated markers with Western blot analysis, while their morphology and size were assessed by transmission electron microscopy (TEM). Human microglia SV40 were cultured for 24 h and then stimulated with EVs (1 or 5 µg/mL), quantitated as total EV-associated protein, for 24 or 48 h. IL-1ß secretion was measured by ELISA. The results were analyzed using the Mann-Whitney U non-parametric test, and all statistical analyses were performed using Graph Pad Prism 5. RESULTS: EVs were isolated and shown to be spherical structures (about 100 nm) surrounded by a membrane. Total EV-associated protein was found to be significantly increased (p = 0.02) in patients as compared to normotypic controls. EVs (5 µg/mL) isolated from the serum of patients with ASD stimulated cultured human microglia to secrete significantly more of the pro-inflammatory cytokine interleukin IL-1ß (163.5 ± 13.34 pg/mL) as compared to the control (117.7 ± 3.96 pg/mL, p < 0.0001). The amount of mitochondrial DNA (mtDNA7S) contained in EVs from children with ASD was found to be increased (p = 0.046) compared to the normotypic controls. CONCLUSIONS: These findings provide novel information that may help explain what triggers inflammation in the brain of children with ASD and could lead to novel effective treatments.

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome-Metabolic Disease or Disturbed Homeostasis due to Focal Inflammation in the Hypothalamus?

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex disease characterized by debilitating fatigue, lasting for at least 6 months, with associated malaise, headaches, sleep disturbance, and cognitive impairment, which severely impacts quality of life. A significant percentage of ME/CFS patients remain undiagnosed, mainly due to the complexity of the disease and the lack of reliable objective biomarkers. ME/CFS patients display decreased metabolism and the severity of symptoms appears to be directly correlated to the degree of metabolic reduction that may be unique to each individual patient. However, the precise pathogenesis is still unknown, preventing the development of effective treatments. The ME/CFS phenotype has been associated with abnormalities in energy metabolism, which are apparently due to mitochondrial dysfunction in the absence of mitochondrial diseases, resulting in reduced oxidative metabolism. Such mitochondria may be further contributing to the ME/CFS symptomatology by extracellular secretion of mitochondrial DNA, which could act as an innate pathogen and create an autoinflammatory state in the hypothalamus. We propose that stimulation of hypothalamic mast cells by environmental, neuroimmune, pathogenic and stress triggers activates microglia, leading to focal inflammation in the brain and disturbed homeostasis. This process could be targeted for the development of novel effective treatments.

TNF stimulates IL-6, CXCL8 and VEGF secretion from human keratinocytes via activation of mTOR, inhibited by tetramethoxyluteolin.

Psoriasis is an autoimmune skin disease characterized by keratinocyte hyperproliferation and chronic inflammation. The pathogenesis of psoriasis involves proinflammatory cytokines, such as tumor necrosis factor (TNF), but the mechanism of keratinocyte activation is not well understood. Here, we show that TNF (10 or 50 ng/mL) stimulates a significant (P < .0001) gene expression and secretion of proinflammatory IL-6, CXCL8 and VEGF from both cultured human HaCaT and normal epidermal human keratinocytes (NHEKs). This effect occurs via activation of the mammalian target of rapamycin (mTOR) signalling complex as shown by Western blot analysis and phospho-ELISAs. Pretreatment with the novel natural flavonoid tetramethoxyluteolin (10-100 µmol L-1 ) significantly (P < .0001) inhibits gene expression and secretion (P < .0001) of all 3 mediators in a concentration-dependent manner. Moreover, tetramethoxyluteolin (50 µmol L-1 ) appears to be a potent inhibitor of the phosphorylated mTOR substrates (pmTORSer2448 , pp70S6KThr389 and p4EBP1Thr37/46 ) as compared to known mTOR inhibitors in keratinocytes. The present findings indicate that TNF stimulates skin inflammation via mTOR signalling. Inhibition by tetramethoxyluteolin may be used in the treatment for psoriasis.

Interleukin 33 and interleukin 4 regulate interleukin 31 gene expression and secretion from human laboratory of allergic diseases 2 mast cells stimulated by substance P and/or immunoglobulin E.

BACKGROUND: Cytokine interleukin (IL) 31 has emerged as an important component of allergic and inflammatory diseases associated with pruritus, such as atopic dermatitis (AD) and mastocytosis. Mast cells (MC) are stimulated by allergic and nonallergic triggers, and play a critical role in such diseases by secreting histamine and tryptase as well as cytokines and chemokines. IL-33 has been reported to augment MC responses, but its effect on secretion of IL-31 is not known. OBJECTIVES: To investigate whether IL-33 can stimulate the secretion of IL-31 from cultured human MCs and whether this response is augmented by either the neuropeptide substance P (SP) or immunoglobulin E (IgE) and anti-IgE in the absence or presence of IL-4. METHODS: Laboratory of Allergic Diseases (LAD2) human MCs were cultured in StemProH-34 SFM medium supplemented by stem cell factor and were stimulated either with IL-33 (10 ng /mL) or SP (2 µM), or preincubated with IgE (1 µg/mL) overnight, and then stimulated with anti-IgE (1 µg/mL) for 24 hours. IL-31 gene expression was measured by quantitative polymerase chain reaction, and protein was measured by enzyme-linked immunosorbent assay. RESULTS: IL-33 (10 ng/mL) induces IL-31 gene expression, synthesis, and secretion from LAD2 cells in the absence of degranulation, whereas SP and IgE on their own have no effect. However, the effect of IL-33 is augmented by SP (2 µM) and/or IgE and anti-IgE (1 µg/mL both) and especially their combination. Moreover, this response is significantly further increased when LAD2 cells are cultured in the presence of IL-4. CONCLUSION: These findings provide evidence that IL-33 induced secretion of IL-31 from LAD2 MC, an action augmented by novel neuroimmune interactions that may help in the development of new treatments of allergic and inflammatory diseases, especially AD and mastocytosis.

Neuropeptides CRH, SP, HK-1, and Inflammatory Cytokines IL-6 and TNF Are Increased in Serum of Patients with Fibromyalgia Syndrome, Implicating Mast Cells.

Fibromyalgia syndrome (FMS) is a chronic, idiopathic condition of widespread musculoskeletal pain affecting more women than men. Even though clinical studies have provided evidence of altered central pain pathways, the lack of definitive pathogenesis or reliable objective markers has hampered development of effective treatments. Here we report that the neuropeptides corticotropin-releasing hormone (CRH), substance P (SP), and SP-structurally-related hemokinin-1 (HK-1) were significantly (P = 0.026, P < 0.0001, and P = 0.002, respectively) elevated (0.82 ± 0.57 ng/ml, 0.39 ± 0.18 ng/ml, and 7.98 ± 3.12 ng/ml, respectively) in the serum of patients with FMS compared with healthy controls (0.49 ± 0.26 ng/ml, 0.12 ± 0.1 ng/ml, and 5.71 ± 1.08 ng/ml, respectively). Moreover, SP and HK-1 levels were positively correlated (Pearson r = 0.45, P = 0.002) in FMS. The serum concentrations of the inflammatory cytokines interleukin (IL)-6 and tumor necrosis factor (TNF) were also significantly (P = 0.029 and P = 0.006, respectively) higher (2.97 ± 2.35 pg/ml and 0.92 ± 0.31 pg/ml, respectively) in the FMS group compared with healthy subjects (1.79 ± 0.62 pg/ml and 0.69 ± 0.16 pg/ml, respectively). In contrast, serum IL-31 and IL-33 levels were significantly lower (P = 0.0001 and P = 0.044, respectively) in the FMS patients (849.5 ± 1005 pg/ml and 923.2 ± 1284 pg/ml, respectively) in comparison with healthy controls (1281 ± 806.4 pg/ml and 3149 ± 4073 pg/ml, respectively). FMS serum levels of neurotensin were not different from controls. We had previously shown that CRH and SP stimulate IL-6 and TNF release from mast cells (MCs). Our current results indicate that neuropeptides could stimulate MCs to secrete inflammatory cytokines that contribute importantly to the symptoms of FMS. Treatment directed at preventing the secretion or antagonizing these elevated neuroimmune markers, both centrally and peripherally, may prove to be useful in the management of FMS.

Fibromyalgia syndrome in need of effective treatments.

Fibromyalgia syndrome (FMS) is a chronic, idiopathic condition of widespread musculoskeletal pain, affecting primarily women. It is clinically characterized by chronic, nonarticular pain and a heightened response to pressure along with sleep disturbances, fatigue, bowel and bladder abnormalities, and cognitive dysfunction. The diagnostic criteria have changed repeatedly, and there is neither a definitive pathogenesis nor reliable diagnostic or prognostic biomarkers. Clinical and laboratory studies have provided evidence of altered central pain pathways. Recent evidence suggests the involvement of neuroinflammation with stress peptides triggering the release of neurosenzitizing mediators. The management of FMS requires a multidimensional approach including patient education, behavioral therapy, exercise, and pain management. Here we review recent data on the pathogenesis and propose new directions for research and treatment.