Objective: Although one of the current hypotheses of the aetiology of fibromyalgia (FM) syndrome involves inflammatory and neuroendocrine disorders, its biophysiology still remains unclear. The purpose of the present investigation was to study the systemic inflammatory and stress responses, as well as the innate response mediated by monocytes and neutrophils in FM patients. Methods: Twenty-five women diagnosed with primary FM and 20 age-matched healthy women (control group) were enrolled in the study. Circulating ‘neuroendocrine-stress’ biomarkers (CRH, ACTH, cortisol, NA, eHsp72, serotonin and IGF-1) were evaluated by ELISA. Serum IL-8 and CRP concentrations were also determined by ELISA, and inflammatory cytokine release by monocytes [IL-1β, TNFα, IL-6, IL-10, IL-18, monocyte chemotactic protein-1 (MCP-1) and RANTES] was evaluated by the Luminex BioPlex system. The phagocytic process of neutrophils (chemotaxis, phagocytosis and microbicide capacity) was also evaluated. Results: FM patients showed an inflammatory state accompanied by an altered stress response. This is mainly manifested by high circulating levels of IL-8 and CRP (in 100% of the FM group), high circulating levels of cortisol, and increased systemic levels of NA and eHsp72. There is also increased release of inflammatory cytokines (IL-1β, TNFα, IL-6, IL-10, IL-18 and MCP-1) by monocytes, and enhanced activation of the functional capacity of neutrophils (chemotactic, phagocytic and fungicidal activities). Conclusion: An inflammatory/stress feedback dysregulation underlies FM. Whether dysregulation of the stress response is the cause of the inflammatory dysregulation or vice versa is also discussed.

Keywords:
IL-8, CRP IL-18, Monocyte chemotactic protein-1, Hsp72, Noradrenaline, Cortisol, Neutrophils, Monocytes, RANTES
1.
Wolfe F, Smythe HA, Yunus MB, Bennett RM, Bombardier C, Goldenberg DL, Tugwell P, Campbell SM, Abeles M, Clark P, et al.: The American College of Rheumatology 1990 Criteria for the Classification of Fibromyalgia. Report of the Multicenter Criteria Committee. Arthritis Rheum 1990;33:160–172.
2.
Van West D, Maes M: Neuroendocrine and immune aspects of fibromyalgia. BioDrugs 2001;15:521–531.
3.
Müller W, Schneider EM, Stratz T: The classification of fibromyalgia syndrome. Rheumatol Int 2007;27:1005–1010.
4.
Giesecke T, Williams DA, Harris RE, Cupps TR, Tian TX, Gracely RH, Clauw DJ: Subgrouping of fibromyalgia patients on the basis of pressure-pain thresholds and psychological factors. Arthritis Rheum 2003;48:2916–2922.
5.
Wallace DJ, Linker-Israeli M, Hallegua D, Silverman S, Silver D, Weisman MH: Cytokines play an aetiopathogenetic role in fibromyalgia: a hypothesis and pilot study. Rheumathology 2001;40:743–749.
6.
Gür A, Karakoç M, Nas K, Cevik R, Denli A, Saraç J: Cytokines and depression in cases with fibromylagia. J Rheumatol 2002;29:358–361.
7.
Wang H, Moser M, Schiltenwolf M, Buchner M: Circulating cytokine levels compared to pain in patients with fibromyalgia: a prospective longitudinal study over 6 months. J Rheumatol 2008;35:1366–1370.
8.
Ortega E, García JJ, Bote ME, Martín-Cordero L, Escalante Y, Saavedra JM, Northoff H, Giraldo E: Exercise in fibromialgia and related inflammatory disorders: known effects and unknown chances. Exerc Immunol Rev 2009;15:42–65.
9.
Ortega E, Bote E, Giraldo E, García JJ: Aquatic exercise improves the monocyte pro- and anti-inflammatory cytokine production balance in fibromyalgia patients. Scand J Med Sci Sports 2012;22:104–112.
10.
Ortega E: Why exercise can improve the symptoms of fibromyalgia? (in Spanish.) Med Clin 2011;137:405–407.
11.
Ortega E, Forner MA, Barriga C: Exercise-induced stimulation of murine macrophage chemotaxis: role of corticosterone and prolactin as mediators. J Physiol 1997;498:729–734.
12.
Boyden S: The chemotaxis effect of mixtures of antibody and antigen on polymorphonuclear leukocyte. J Exp Med 1962;115:453–456.
13.
Ortega E, Collazos ME, Maynar M, Barriga C: Stimulation of the phagocytic function of neutrophils in sedentary men alters acute moderate exercise. Eur J Appl Physiol Occup Physiol 1993;66:60–64.
14.
Giraldo E, Martín-Cordero L, García JJ, Gerhmann M, Multhoff G, Ortega E: Exercise-induced extracellular 72 kDa heat shock protein (Hsp72) stimulates neutrophil phagocytic and fungicidal capacities via TLR-2. Eur J Appl Physiol 2010;108:217–225.
15.
García JJ, Bote E, Hinchado MD, Ortega E: A single session of intense exercise improves the inflammatory response in healthy sedentary women. Physiol Biochem 2011;67:87–94.
16.
Cunha FQ, Lorenzetti BB, Poole S, Ferreira SH. Interleukin-8 as a mediator of sympathetic pain. Br J Pharmacol 1991;104:765–767.
17.
Bazzichi L, Rossi A, Massimetti G, Giannaccini G, Giuliano T, De Feo F, Ciapparelli A, Dell’Osso L, Bombardieri S: Cytokine patterns in fibromyalgia and their correlation with clinical manifestations. Clin Exp Rheumatol 2007;25:225–230.
18.
Gür A, Oktayoglu P: Status of immune mediators in fibromyalgia. Curr Pain Headache Rep 2008;12:175–181.
19.
Crofford LJ, Young EA, Engleberg NC, Korszum A, Brucksch CB, McClure LA, Brown MB, Demitrack MA: Basal circadian and pulsatile ACTH and cortisol secretion in patients with fibromyalgia and/or chronic fatigue syndrome. Brain Behav Immun 2004;18:314–325.
20.
Geiss A, Rohleder N, Anton F: Evidence for an association between an enhanced reactivity of interleukin-6 and reduced glucocorticoid sensitivity in patients with fibromyalgia. Psychoneuroendocrinology 2012;37:671–684.
21.
Lindquist S, Craig EA: The heat-shock proteins. Annu Rev Genet 1988;22:631–677.
22.
Ortega E, Hinchado MD, Martín-Cordero L, Asea A: The effect of stress-inducible extracllular Hsp72 on human neutrophil chemotaxis: a role during acute intense exercise. Stress 2009;12:240–249.
23.
Fleshner M, Campisi J, Amiri L, Diamond DM: Cat exposure induces both intra- and extracellular Hsp72: the role of adrenal hormones. Psychoneuroendocrinology 2004;29:1142–1152.
24.
Campisi J, Leem TM, Fleshner M: Stress-induced extracellular Hsp72 is a functionally significant danger signal to the immune system. Cell Stress Chaperones 2003;8:272–286.
25.
Giraldo E, Multhoff G, Ortega E: Noradrenaline increases the expression and release of Hsp72 by human neutrophils. Brain Behav Immun 2010;24:672–677.
26.
Wolfe F, Russell IJ, Vipraio G, Ross K, Anderson J: Serotonin levels, pain threshold, and fibromyalgia symptoms in the general population. J Rheumatol 1997;24:555–559.
27.
Ernberg M, Lundeberg T, Kopp S: Effects on muscle pain by intramuscular injection of granisetron in patients with fibromyalgia. Pain 2003;101:275–282.
28.
Di Franco M, Iannuccelli C, Atzeni F, Cazzola M, Salaffi F, Valesini G, Sarzi-Puttini: Pharmacological treatment of fibromyalgia. Clin Exp Rheumatol 2010;28:110–116.
29.
Bennett RM, Clark SC, Walczyk J: A randomized, double-blind, placebo-controlled study of growth hormone in the treatment of fibromyalgia. Am J Med 1998;104:227–231.
30.
McCall-Hosenfeld JS, Goldenberg DL, Hurwitz S, Adler GK: Growth hormone and insulin-like growth factor-1 concentrations in women with fibromyalgia. J Rheumatol 2003;30:809–814.
31.
Bennett RM, Cook DM, Clark SR, Burckhardt CS, Campbell SM: Hypothalamic-pituitary-insulin-like growth factor-I axis dysfunction in patients with fibromyalgia. J Rheumatol 1997;24:1384–1389.
32.
Cuatrecasas G, Riudavets C, Güell MA, Nadal A: Growth hormone as concomitant treatment in severe fibromialgia associated with low IGF-1 serum levels: a pilot study. BMC Musculoskelet Disord 2007;8:119.
33.
Dinarello CA, Novick D, Puren AJ, Fantuzzi G, Shapiro L, Mühl H, Yoon DY, Reznikov LL, Kim SH, Rubinstein M: Overview of interleukin-18: more than an interferon-gamma inducing factor. J Leukoc Biol 1998;63:658–664.
34.
Kohno K, Kurimoto M: Interleukin 18, a cytokine which resembles IL-1 structurally and IL-12 functionally but exerts its effect independently of both. Clin Immunol Immunopathol 1998;86:11–15.
35.
Ferreira AM, Rollins BJ, Faunce DE, Burns AL, Zhu X, Dipietro LA: The effect of MCP-1 depletion on chemokine and chemokine-related gene expression: evidence for a complex network in acute inflammation. Cytokine 2005;30:64–71.
36.
Zhang Z, Cherryholmes G, Mao A, Marek C, Longmate J, Kalos M, Amand, RP, Shively JE: High plasma levels of MPC-1 and eotaxin provide evidence for an immunological basis of fibromyalgia. Exp Biol Med 2008;233:1171–1180.
37.
Blanco I, Janciauskiene S, Nita I, Fernández-Bustillo E, Cárcaba V, Gallo C, Álvarez-Rico M, de Serres F, Béridze N: Low plasma levels of monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor-alpha (TNF-alpha), and vascular endotelial growth factor (VEGF) in patients with alpha1-antitrypsin deficiency-related fibromyalgia. Clin Rheumatol 2010;29:189–197.
38.
Giraldo E, Hinchado MD, García JJ, Ortega E: Influence of gender and oral contraceptives intake on innate and inflammatory response: role of neuroendocrine factors. Mol Cell Biochem 2008;313:147–153.
39.
Garrison RL, Breeding PC: A metabolic basis for fibromyalgia and its related disorders: the possible role of resistance to thyroid hormone. Med Hypotheses 2003;61:182–189.
40.
Ortega E, Giraldo E, Hinchado MD, Martinez M, Ibáñez S, Cidoncha A, Collazos ME, García JJ: Role of Hsp72 and norepinephine in the moderate exercise-induced stimulation of neutrophils’ microbicide capacity. Eur J Appl Physiol 2006;98:250–255.
41.
Ortega E, Giraldo E, Hinchado MD, Marín L, García JJ, De la Fuente M: Neuroinmmunomodulation during exercise: role of catecholamines as ‘stress mediator’ and/or ‘danger signal’ for the innate immune response. Neuroinmmunomodulation 2007;98:250–255.
42.
Ortega E, Giraldo E, Hinchado MD, Martín-Cordero L, García JJ: 72 kDa extracellular heat shock protein (eHsp72), norepinephrine (NE), and the innate immune response following moderate exercise; in Asea A, Pedersen BK (eds): Heat Shock Proteins and Whole Body Physiology. New York, Springer, 2010, pp 329–350.
43.
Kaufmann I, Schelling G, Eisner C, Richter HP, Krauseneck T, Vogeser M, Hauer D, Campolongo P, Chouker A, Beyer A, Thiel M: Anandamide and neutrophils function in patients with fibromyalgia. Psychoneuroendocrinology 2008;33:676–685.
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