Nerve Growth Factor and Selected Cytokines in Women With and Without Vulvodynia

Objective The aim of the study was to assess the association between cytokines/neurokines after in vitro stimulation with Candida antigen or lipopolysaccharide (LPS) in blood samples among women with and without vulvodynia. Materials and Methods Women with vulvodynia and asymptomatic controls at three offices at the University of Michigan were examined clinically and completed a comprehensive survey in this cross-sectional study. Cytokine/neurokine levels were determined on blood samples using established ELISA protocols. Analysis of 48 cases and 42 ethnically matched controls included descriptive statistics (median, minimal, and maximal levels of cytokines/neurokines), overall and in cases and controls. Because of left-censored measurements, interval censored survival analysis was used to assess the association between case/control status and pain characteristics with cytokine/neurokine levels. Results Participants ranged in age from 19 to 60 years. Levels of IL1&bgr;, IL1-RA, TNF&agr;, IL-6, and IL-8 increased substantially after LPS stimulation, whereas no response was seen on IFN&ggr; or nerve growth factor (NGF). Each increased after Candida antigen stimulation, although responses to Candida antigen stimulation of IL1&bgr;, IL-6, and TNF&agr; were less robust than after LPS. Only NGF was significantly increased in vulvodynia cases compared with controls (Exp &bgr; (95% CI) = 2.08 [1.08–3.98]) after 24-hour Candida antigen stimulation and persisted when controlled for age, use of oral contraceptives, or history of Candida vulvovaginitis. No association between cytokine/neurokine levels and pain characteristics was found. Conclusions Compared with that of control women, whole blood from women with vulvodynia demonstrates an enhanced production of NGF, but not of a set of inflammation-related cytokines, in response to Candida antigen stimulation.

[1]  A. Rapkin,et al.  Catechol‐O‐methyltransferase gene polymorphism and vulvar pain in women with vulvodynia , 2017, American journal of obstetrics and gynecology.

[2]  A. Paetau,et al.  Immune activation enhances epithelial nerve growth in provoked vestibulodynia. , 2016, American journal of obstetrics and gynecology.

[3]  T. Peresleni,et al.  Inflammatory Markers in Vestibulodynia , 2016 .

[4]  C. Crum,et al.  Vestibular Mast Cell Density in Vulvodynia: A Case-Controlled Study , 2016, Journal of lower genital tract disease.

[5]  J. Bornstein,et al.  2015 ISSVD, ISSWSH, and IPPS Consensus Terminology and Classification of Persistent Vulvar Pain and Vulvodynia , 2016, Journal of lower genital tract disease.

[6]  Ananda Sen,et al.  Remission, Relapse, and Persistence of Vulvodynia: A Longitudinal Population-Based Study. , 2016, Journal of women's health.

[7]  G. Bachmann,et al.  Vulvodynia: Definition, Prevalence, Impact, and Pathophysiological Factors. , 2016, The journal of sexual medicine.

[8]  David A. Williams,et al.  Presence of Spontaneous Pain and Comorbid Pain Conditions Identifies Vulvodynia Subgroups , 2016, Journal of lower genital tract disease.

[9]  C. Haidaris,et al.  Identification of novel mechanisms involved in generating localized vulvodynia pain. , 2015, American journal of obstetrics and gynecology.

[10]  C. Beham‐Schmid,et al.  Mast cell infiltrates in vulvodynia represent secondary and idiopathic mast cell hyperplasias , 2015, Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS).

[11]  S. Meri,et al.  Activation of vestibule-associated lymphoid tissue in localized provoked vulvodynia. , 2015, American journal of obstetrics and gynecology.

[12]  E. Baştu,et al.  Elevated tissue levels of tumor necrosis factor-α in vulvar vestibulitis syndrome. , 2014, Clinical and experimental obstetrics & gynecology.

[13]  T. Morgan,et al.  CD4-Positive T-Cell Recruitment in Primary-Provoked Localized Vulvodynia: Potential Insights into Disease Triggers , 2014, Journal of lower genital tract disease.

[14]  D. Smolenski,et al.  Latent class analysis of comorbidity patterns among women with generalized and localized vulvodynia: preliminary findings , 2013, Journal of pain research.

[15]  B. Mahal,et al.  NGF – the TrkA to successful pain treatment , 2012, Journal of pain research.

[16]  Ananda Sen,et al.  Relationship Between Vulvodynia and Chronic Comorbid Pain Conditions , 2012, Obstetrics and gynecology.

[17]  Hong Li,et al.  Histologic and receptor analysis of primary and secondary vestibulodynia and controls: a prospective study. , 2010, American journal of obstetrics and gynecology.

[18]  D. Buchwald,et al.  Evidence for overlap between urological and nonurological unexplained clinical conditions. , 2009, The Journal of urology.

[19]  S. Fan,et al.  Vaginal allergic response in women with vulvovaginal candidiasis , 2008, International journal of gynaecology and obstetrics: the official organ of the International Federation of Gynaecology and Obstetrics.

[20]  J. Bornstein,et al.  Involvement of Heparanase in the Pathogenesis of Localized Vulvodynia , 2008, International journal of gynecological pathology : official journal of the International Society of Gynecological Pathologists.

[21]  W. Ledger,et al.  Association between primary vulvar vestibulitis syndrome, defective induction of tumor necrosis factor-alpha, and carriage of the mannose-binding lectin codon 54 gene polymorphism. , 2008, American journal of obstetrics and gynecology.

[22]  C. Haidaris,et al.  Enhanced synthesis of proinflammatory cytokines by vulvar vestibular fibroblasts: implications for vulvar vestibulitis. , 2007, American journal of obstetrics and gynecology.

[23]  S. Omoigui.  The biochemical origin of pain: the origin of all pain is inflammation and the inflammatory response. Part 2 of 3 - inflammatory profile of pain syndromes. , 2007, Medical hypotheses.

[24]  G. Bachmann,et al.  Vulvodynia: Characteristics and Associations With Comorbidities and Quality of Life , 2006, Obstetrics and gynecology.

[25]  Stephen B. McMahon,et al.  Immune and glial cell factors as pain mediators and modulators , 2005, Experimental Neurology.

[26]  D. Jurič,et al.  Corrigendum to “Differences in the regulation of BDNF and NGF synthesis in cultured neonatal rat astrocytes” [Int. J. Dev. Neurosci. 22 (2004) 119–130] , 2005, International Journal of Developmental Neuroscience.

[27]  I. Ben‐Ami,et al.  The Major Histopathologic Characteristics in the Vulvar Vestibulitis Syndrome , 2005, Gynecologic and Obstetric Investigation.

[28]  J. Bornstein,et al.  Hyperinnervation and Mast Cell Activation May Be Used as Histopathologic Diagnostic Criteria for Vulvar Vestibulitis , 2004, Gynecologic and Obstetric Investigation.

[29]  W. Ledger,et al.  Altered distribution of mannose-binding lectin alleles at exon I codon 54 in women with vulvar vestibulitis syndrome. , 2004, American journal of obstetrics and gynecology.

[30]  D. Foster,et al.  Impact of genetic variation in interleukin-1 receptor antagonist and melanocortin-1 receptor genes on vulvar vestibulitis syndrome. , 2004, The Journal of reproductive medicine.

[31]  P. Anand,et al.  Increased vanilloid receptor VR1 innervation in vulvodynia , 2004, European journal of pain.

[32]  G. Terenghi,et al.  Increased innervation of the vulval vestibule in patients with vulvodynia , 2003, The British journal of dermatology.

[33]  W. Ledger,et al.  Interleukin-1beta gene polymorphism in women with vulvar vestibulitis syndrome. , 2003, European journal of obstetrics, gynecology, and reproductive biology.

[34]  W. Ledger,et al.  Defective regulation of the proinflammatory immune response in women with vulvar vestibulitis syndrome. , 2002, American journal of obstetrics and gynecology.

[35]  W. Ledger,et al.  Influence of interleukin-1 receptor antagonist gene polymorphism on disease. , 2002, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[36]  W. Ledger,et al.  A deficiency in interferon-alpha production in women with vulvar vestibulitis. , 2002, American journal of obstetrics and gynecology.

[37]  Maria Torcia,et al.  Nerve Growth Factor Inhibits Apoptosis in Memory B Lymphocytes via Inactivation of p38 MAPK, Prevention of Bcl-2 Phosphorylation, and Cytochrome c Release* , 2001, The Journal of Biological Chemistry.

[38]  M. Hilliges,et al.  The expression of cyclooxygenase 2 and inducible nitric oxide synthase indicates no active inflammation in vulvar vestibulitis , 2001, Acta obstetricia et gynecologica Scandinavica.

[39]  S. Witkin,et al.  Interleukin 1 receptor antagonist gene polymorphism in women with vulvar vestibulitis. , 2000, American journal of obstetrics and gynecology.

[40]  M. Hilliges,et al.  Increased Intraepithelial Innervation in Women with Vulvar Vestibulitis Syndrome , 1998, Gynecologic and Obstetric Investigation.

[41]  W. I. van der Meijden,et al.  Histopathologic Features of Vulvar Vestibulitis , 1998, International journal of gynecological pathology : official journal of the International Society of Gynecological Pathologists.

[42]  J. Sobel,et al.  Vaginal-associated immunity in women with recurrent vulvovaginal candidiasis: evidence for vaginal Th1-type responses following intravaginal challenge with Candida antigen. , 1997, The Journal of infectious diseases.

[43]  J. Hasday,et al.  Elevated tissue levels of interleukin‐1β and tumor necrosis factor‐alpha in vulvar vestibulitis , 1997, Obstetrics and gynecology.

[44]  C. Woolf,et al.  Peripheral cell types contributing to the hyperalgesic action of nerve growth factor in inflammation , 1996, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[45]  M. Kohno,et al.  Tumor necrosis factor is markedly synergistic with interleukin 1 and interferon‐γ in stimulating the production of nerve growth factor in fibroblasts , 1994, FEBS letters.

[46]  D. Remick,et al.  Biphasic production of IL-8 in lipopolysaccharide (LPS)-stimulated human whole blood. Separation of LPS- and cytokine-stimulated components using anti-tumor necrosis factor and anti-IL-1 antibodies. , 1992, Journal of immunology.

[47]  D. Remick,et al.  Kinetics of TNF, IL-6, and IL-8 gene expression in LPS-stimulated human whole blood. , 1991, Biochemical and biophysical research communications.