Monocyte expression levels of cytokines in patients with fibromyalgia syndrome.
Some dissimilar results have been obtained in studies aiming to investigate the relationship of cytokines with FMS symptoms and their role in etiopathogenesis. (10,13) We relate these conflicts to different measurement methods of cytokines and whether the cytokines were measured directly or indirectly. Thus, in this study, we aimed to determine monocyte expression levels of IL-1[beta], IL-6, IL-8, and TNF-[alpha] in FMS patients and healthy females.
PATIENTS AND METHODS
A total of 80 female FMS patients, who applied to Gaziantep University Faculty of Medicine Sahinbey Research and Application Hospital Department of Physical Medicine and Rehabilitation Polyclinic between March 2010 and April 2011, and 50 healthy females, who did not have any systemic diseases and showed similarities with the patient group in terms of age and demographic characteristics, were included in the study. Twelve of the FMS patients who did not meet the 1990 American College of Rheumatology criteria and 10 healthy controls were excluded. After exclusion 68 participants as FMS patient (mean age 41.41 [+ or -] 7.14 years; range 18 to 55 years) and 40 participants as control group (mean age 39.12 [+ or -] 10.9 years; range 18 to 55 years) were included in the study.
Exclusion criteria included psychiatric disease history such as schizophrenia, paranoia, somatoform disorder etc., immune deficiency, malignity, diabetes mellitus, hypo/hyperthyroid, chronic infection and inflammation (tuberculosis, rheumatoid arthritis, systemic lupus erythematous, ulcerative colitis, Crohn disease, ankylosing spondylitis etc.), cardiac and renal disease, pregnant and lactating females, having had a major trauma and surgical operation and taken serotonin reuptake inhibitors such as fluoxetine in the last six weeks, agents such as monoamine oxidase inhibitors activating central nerve system in the last two weeks, and non-steroid anti-inflammatory drugs and acetaminophen etc. in the last week. The study was executed thanks to the support of the Scientific Research Fund following the approval of the Ethics Committee of Gaziantep University, Faculty of Medicine (project no: TF.10.29) and informed consent of all participants were obtained.
Each member from both groups filled in and signed a detailed survey form that queries age, marital status, height, weight, body mass index (BMI), educational status, 10 cm visual analog scale, patient's and physician's global assessment of disease severity, fibromyalgia impact questionnaire (FIQ), Hamilton anxiety and depression assessment scale (HAM-A and HAM-D, respectively), modified fatigue impact scale (MFIS), and Nottingham health profile scale. Members of both groups were surveyed about morning stiffness at joints, chronic pain, local pain, reflected pain, subjective swelling history at joints, non-refreshing sleep, paresthesia, fatigue, female urethral syndrome, Raynaud phenomenon, distress, headache, dysmenorrhea, irritable bowel syndrome, depression, allergic rhinitis, and sicca complex.
Fibromyalgia impact questionnaire measures 10 different factors namely physical function, feeling well, not being able to go to work, having challenges at work, pain, fatigue, morning fatigue, stiffness, anxiety and depression. Except for feeling well, low scores indicate improvement and being less affected by disease. The possible maximum score for every subheading is 10. Thus, the total maximum score is 100. (14)
Modified fatigue impact scale evaluates fatigue by 21 questions. It consists of three subsections. Each question is scored between 0 to 4 points. Total score is between 0 to 84. The highest score gives the most severe fatigue value. (15)
Visual analog scale is used for the assessment of pain severity. The scale is 10 cm long and the patient marks the point (0= no pain, 10= the most severe pain) on a vertical or horizontal line corresponding to severity of the pain.
Patient's and physician's global assessment of disease severity require the patient and physician to evaluate the disease severity. It progresses from 0 to 10. Zero means no pain and 10 means very severe pain.
Nottingham Health Profile evaluates health condition. Subheadings provide information about the activity of the patient. It consists of 38 questions regarding pain (eight questions), physical activity (eight questions), fatigue (three questions), sleep (five questions), social isolation (five questions), and emotional reactions (nine questions). Questions are answered as yes/no. Scores range between 0 (the best score) and 100 (the worst score). (16)
Hamilton Depression Scale assesses depression level of the patient. It consists of 17 questions and 14 points and over indicate depression. (17) HAM-A has been arranged to determine the anxiety level and distribution of indications and to measure severity change. It consists of 14 items which question both mental and physical indications. Existence and severity of the items in the scale are evaluated by the interviewer. (18)
Analyses were performed on mononuclear cells in whole blood or peripheral blood samples taken from patient and control groups between 08:30 to 09:30 hours and placed into ethylenediaminetetraacetic acid tubes.
1. Brefeldin A was prepared with 5 mg/mL dimethyl sulfoxide (BD Biosciences, San Jose, CA, USA).
2. Lipopolysaccharide (LPS) was prepared with 5 mg/mL dimethyl sulfoxide/phosphate buffered saline (PBS).
3. Monoclonal antibodies. CD14 antibody was used to express monocytes.
4. Fluorescence-activated cell sorting (FACS) lysing solution (10X) was diluted with 1:10 deionized water (BD Biosciences, San Jose, CA, USA).
5. Fluorescence-activated cell sorting permeabilizing solution (10X) was diluted with 1: 10 deionized water (BD Biosciences, San Jose, CA, USA).
6. Irrigation solution (Wash Buffer-PBS).
7. Fast immune anti-cytokine and control monoclonal antibodies (BD Biosciences, San Jose, CA, USA).
8. 1% paraformaldehyde.
Two different groups as unstimulated and activated cultures were prepared for monocyte activation. Unstimulated tubes were prepared by adding 500 [micro]L Roswell Park Memorial Institute (RPMI) solution and 2 [micro]L brefeldin A (BD Biosciences, San Jose, CA, USA) into 500 [micro]L whole blood with ethylenediaminetetraacetic acid. Activated tubes were prepared by adding 500 [micro]L RPMI solution and 2 [micro]L brefeldin A (BD Biosciences, San Jose, CA, USA) and 2 [micro]L LPS into 500 [micro]L whole blood with ethylenediaminetetraacetic acid. Tubes prepared for both groups were vortexed and incubated in 7% carbon dioxide incubator at 37[degrees]C for four hours.
At the end of incubation, 50 [micro]L blood and 5 [micro]L CD14 antibody were included in Falcon tubes (Taizhou Runlab Labware Manufacturing Co., Ltd., Shaoxing, China) prepared for both groups and these were vortexed. They were incubated for 15-30 minutes at room temperature in the dark. At the end of incubation, 2 mL 1X FACS Lysing Solution (BD Biosciences, San Jose, CA, USA) was included in the tubes, they were vortexed and incubated for 10 minutes at room temperature in the dark. Upon completion of incubation time, tubes were centrifuged at 1,500 rpm for five minutes and the supernatant was removed. 500 [micro]L 1X FACS Permeabilizing solution (BD Biosciences, San Jose, CA, USA) was included on the pallet, it was vortexed and incubated for 10 minutes at room temperature in the dark. Two to 4 mL PBS was added to them, they were centrifuged at 1,500 rpm for five minutes and the supernatant was removed. Five microliter 1% fluorescent conjugated monoclonal antibodies (TNF-[alpha], IL-6, IL-8, IL-1[beta]) (BD Biosciences, San Jose, CA, USA) were included on the pallets; they were centrifuged for 30 minutes at room temperature in the dark. At the end of incubation time, 2 to 4 mL PBS was added into Falcon tubes, they were centrifuged at 1,500 rpm for five minutes and the supernatants were removed. 500 [micro]L 1% paraformaldehyde was added into the pellets. The prepared tubes were read by FACS Flow Cytometry (FACSCalibur, BD Biosciences, San Diego, CA, USA) and analyzed. One of the results is provided as an example in Figure 1.
Statistical analysis of data was performed using SPSS for Windows version 15.0 software program (SPSS Inc., Chicago, IL, USA). Chi square test was used to evaluate the difference between groups in terms of categorical variables. Data were normally distributed. Student t-test was used to compare mean values of the patient and the control groups. Correlations between different variables were analyzed by Pearson rank correlation. Statistical significance level was determined as 0.05.
No statistically significant difference was detected between the two groups in terms of average age, BMI, and other demographic data (p > 0.05). BMIs of the patient and the control groups were 28.52 [+ or -] 4.39 and 26.92 [+ or -] 6.38, respectively which indicated no significant difference between the two groups (p > 0.05). Demographic characteristics of the patient and the control groups are presented in Table 1. Prevalence of morning stiffness at joints, chronic pain, reflected pain, fatigue, non-refreshing sleep, subjective swelling history at joints, paresthesia, distress, headache, dysmenorrhea, irritable colon syndrome, and depression was higher and statistically significant in FMS patient group compared to the control group (p < 0.05) (Table 2).
Patient's and physician's global assessment of disease severity, visual analog scale, HAM-A, HAM-D, FIQ, MFIS total score, and Nottingham health profile-total subscore values were significantly higher in the patient group than the control group (p < 0.001) (Table 3). There was no significant difference between the groups in terms of expression values of TNF-[alpha], IL-1[beta], IL-6, and IL-8 (p > 0.05) (Table 4).
Significant positive correlations were shown between cytokines and Nottingham health profile subscales in FMS patients (Table 5). No significant correlations were found between cytokines and visual analog scale, patient's and physician's global assessment of disease activity, FIQ, HAM-A, HAM-D, and MFIS scores (p > 0.05).
Patients with HAM-A and HAM-D scores over 14, FIQ scores between 50 to 69, and FIQ scores over 69 were divided into subgroups. When these subgroups were compared with control group, there was no significant difference in terms of expressed amounts of cytokines (p > 0.05).
Fibromyalgia syndrome is a chronic pain syndrome accompanied by widespread muscle pain, fatigue, and sleep disorder that last longer than three months. There have been multi-lateral researches and discussions on FMS which needs a sophisticated and challenging treatment. One of the prominent theories concerning FMS is that cytokines play a role both in etiology and severity of core systems. Attention towards cytokines as the potential mediator of core symptoms in FMS was drawn when Wallace et al. (19) reported acute onset of FMS symptoms including pain, fatigue, and mental state and sleep disorder in cancer patients receiving IL-2 treatment. Cytokines are immune-modulator proteins and have vast biologic effects. (20) While IL-8 triggers sympathetic pain, IL-6 induces hyperalgesia, fatigue, and depression. IL-1b affects hyperalgesia, fatigue, myalgia, and fever. Finally TNF-[alpha] is known to trigger rapid eye movement sleep, allodynia, and stress. (21)
In the literature, comparison of IL-1b levels in FMS and control groups showed no significant difference, which was also consistent with our study. (6,10,22-25) Four of these studies measured serum levels of IL-1[beta], (10,22-24) while one study measured both serum and cytokine content of PBMCs (6) and another conducted a cytokine expression measurement from PBMCs with a method similar to our FACS. (25)
A study showed that IL-1a levels of FMS patients were too low to be within the measurement range. (26) There was no significant difference between 64 FMS patients and 25 healthy volunteers included in that study in terms of age, sex, ethnic origin, and other demographic data such as educational status and socioeconomic level. However, BMI in FMS patient group was significantly higher than the control group. This might be the reason why the results of that study are different from ours and other studies. Therefore, we tried to include individuals with similar demographical characteristics, i.e. age, sex, BMI, ethnic origin, and educational status, in both groups to prevent the results of our study from being affected by such factors.
In seven studies where IL-6 levels in FMS patients were examined, no significant differences were found between the patient and control groups. (10,22,24,25,27-29) Five of these studies measured serum and plasma concentrations, (10,22,27-29) one measured serum emission levels of IL-6 for 24 hours (while sleeping and awake), (24) and another measured the levels expressed from PBMCs. (25)
Coherent with these studies, we did not obtain a significant difference between the patient and control groups in terms of IL-6 expression from PBMCs at the end of our study. On the other hand, one study reported higher IL-6 levels in FMS patient group than the control group. (6) The difference in this study was related to the applied method where comparison of cytokine generation from PBMCs was made depending on the response of the patient and the control group PBMCs to stimulation with in vitro lectin phytohemagglutinin (PHA) or LPS (with and without phorbol myristic acetate). Researchers demonstrated that the amount of IL-6 produced in patient PBMCs stimulated with LPS was similar with the amount of IL-6 in control group; while in presence of phorbol myristic acetate, the patient PBMCs stimulated with PHA acted differently from the control group.
Various mitogens were used to stimulate cytokine expression in different studies, including phorbol myristate acetate, concanavalin A, and PHA. (21) We used LPS in our study for this purpose. We demonstrated that cytokine expression from PBMCs stimulated with LPS did not show any difference between the patient and the control groups, which was similar to the results of the above-mentioned study. (6) An analysis of the relationship between TNF-[alpha] and FMS revealed that the TNF-[alpha] level of the patient and the control groups were similar in five studies. (6,23-25,30) These studies compared the patient and control groups in terms of serum, (23) serum and simultaneous PBMC generation, (6) 24 hour emission pattern in the plasma, (24) serum and simultaneous messenger ribonucleic acid expressions, (30) and intracellular cytokine levels. (25) TNF-[alpha] levels expressed on the surface of PBMCs of the patient and the control groups were compared in our study and no significant difference was found.
Meanwhile, two studies discovered significantly higher TNF-[alpha] plasma and serum concentrations in FMS patients compared to the control group. (27,28) Single measurement was made in one of these studies (27) whereas regular measurements were made throughout six months in the other. (28)
Contrary to these studies, there are studies which detected a lower TNF-[alpha] level in the patient group. (26) Contradictory results of these studies which compared results from plasma and serum might be arising from the differences in patient selection criteria, number of participants, age, BMI, and measurement methods.
Furthermore, in four studies which examined the relationship between FMS and IL-8 level, (6,10,22,24,25,27-31) there was no significant difference between the measurements of the patient and the control groups. (24,25,29,30) These studies measured emission levels of IL-8 in plasma for 24 hours, (24) intracellular levels of PBMCs stimulated by PHA with the FACS method, (25) with enzyme-linked immunosorbent assay in serum (29) and both enzyme-linked immunosorbent assay in serum and messenger ribonucleic acid expressions simultaneously with polymerase chain reaction. (30) We did not find any significant difference between the levels of IL-8 expressed on the surface of PBMCs in patient and control groups, either.
In other studies in this field, serum and plasma measurements were performed on samples taken only once and IL-8 levels were shown to be high in the patient group. (10,22,27) In another study which found plasma IL-8 levels higher in the patients, no significant difference was detected in patient and control groups in terms of simultaneous in vitro PBMC production levels. (6) In two different studies conducted by the same researcher group, serum IL-8 levels were measured in the samples taken on determined days during the six month monitoring period and were demonstrated to be significantly high in the patient group. (28,31)
Our study had some limitations. First, our sample size was small. We need further comprehensive studies with greater sample size where serum and PMBC related measurements are made together. Additionally, cytokine levels in the cerebrospinal fluid may provide more accurate information.
In many studies including ours where cytokine analyses were performed using methods such as PBMC related cell cytokine content, production levels, surface expression or messenger ribonucleic acid expression, no significant difference was found between the patient and control groups but only high levels of serum/plasma measuring were reported. This suggests that there is no difference in production and expressions from monocytes and there might be other factors affecting their serum/plasma cytokine levels and duration of existence and functions in peripheral structures.
The role of inflammation in fibromyalgia has been the topic of research and debate for decades. The overall literature regarding inflammatory processes in FMS is inconsistent and commonly includes conflicting results. Contradictory results obtained from studies that analyze the role of cytokines in FMS etiopathogenesis might be stemming from patient selection criteria, difference in number of participants, population characteristics, different symptom patterns, differences in measurement methods such as direct measurement or expression levels from serum/plasma or monocytes. Our study indicates that dysregulation of cytokines derived from circulating monocytes is not a dominant factor in the pathogenesis of FMS. Additionally, there was no significant difference in cytokine levels among patients with severe symptoms. However, the role of cytokines in the pathogenesis of FMS may not totally be excluded owing to the results obtained in either ex vivo or in vitro studies which do not necessarily represent the in vivo conditions. Also, symptoms in patients with FMS may be more related to disordered cytokine production by glial cells within the central nervous system than the production of cytokines in the circulation.
Declaration of conflicting interests
The authors declared no conflicts of interest with respect to the authorship and/or publication of this article.
The authors received no financial support for the research and/or authorship of this article.
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Evrim OGUT,  Ali GUR,  Burhan Fatih KOCYIGIT,  Serdar OZTUZCU,  Beyhan CENGIZ,  Ozlem ALTINDAG,  Hilal KARAGULLU,  Savas GURSOY 
 Department of Physical Medicine and Rehabilitation, Erenkoy Physical Medicine and Rehabilitation Hospital, Istanbul, Turkey
 Department of Physical Medicine and Rehabilitation, Medical Faculty of Gaziantep University, Gaziantep, Turkey
 Department of Medical Biology, Medical Faculty of Gaziantep University, Gaziantep, Turkey
 Department of Medical Physiology, Medical Faculty of Gaziantep University, Gaziantep, Turkey
 Department of Physical Medicine and Rehabilitation, Mus State Hospital, Mus, Turkey
Received: October 22, 2014 Accepted: May 09, 2015 Published online: August 10, 2015
Correspondence: Burhan Fatih Kocyigit, MD. Gaziantep Universitesi Tip Fakultesi Hastanesi Fiziksel Tip ve Rehabilitasyon Anabilim Dali, 27310 Sehitkamil, Gaziantep, Turkey. Tel: +90 505 - 906 86 38 e-mail: firstname.lastname@example.org
Table 1. Demographic data of patient and control groups Patients (n=68) Controls (n=40) n % Mean n % Mean Age (years) 41.41 39.12 Body mass index (kg/[m.sup.2]) 28.52 26.92 Educational status Illiterate 5 7.3 0 0 Literate 6 8.8 6 15 Primary school graduate 31 45.5 9 22.5 Secondary school graduate 8 11.7 5 12.5 High school graduate 10 14.7 8 20 University graduate 6 8.8 12 30 Master's/doctor's degree 2 2.9 0 0 Marital status Married 61 89.7 31 77.5 Single 2 2.9 8 20 Widow 2 2.9 1 2.5 Divorced 2 2.9 0 0 Married/lives apart 1 1.4 0 0 Table 2. Symptoms and findings in patient and control groups Patients Controls (n=68) (n=40) n % n % P Morning stiffness in joints 46 67.6 2 5 <0.001 Chronic pain 68 100 8 20 <0.001 Local pain 55 80.8 27 67.5 0.162 Reflected pain 44 64.7 15 37.5 0.009 Subjective swelling history at joints 50 73.5 3 7.5 <0.001 Non-refreshing sleep 64 94.1 7 17.5 <0.001 Paresthesia 55 80.8 8 20 <0.001 Fatigue 67 98.5 25 62.5 <0.001 Woman urethral syndrome 20 29.4 6 15 0.107 Raynaud's phenomenon 0 0 1 2.5 0.37 Distress 62 91.1 14 35 <0.001 Headache 51 75 10 25 <0.001 Dysmenorrhea 26 38.2 7 17.5 0.031 Irritable bowel syndrome 42 61.7 14 35 0.01 Depression 55 80.8 10 25 <0.001 Allergic rhinitis 6 8.8 2 5 0.707 Sicca complex 11 16.1 2 5 0.126 * p < 0.05. Table 3. Clinic characteristics of patient and control groups Patients Mean [+ or -] SD Patient's global assessment of disease 6.17 [+ or -] 1.62 activity, VAS (cm) Physician's global assessment of disease 5.16 [+ or -] 1.14 activity, VAS (cm) Pain severity, VAS (cm) 6.63 [+ or -] 1.72 Fibromyalgia impact questionnaire-total score 51.77 [+ or -] 11.15 Hamilton anxiety assessment scale total score 14.23 [+ or -] 6.40 Hamilton depression assessment scale total 12.51 [+ or -] 5.36 score Modified fatigue impact scale-total score 46.55 [+ or -] 14.58 Nottingham health profile-pain 59.20 [+ or -] 26.38 Nottingham health profile-physical 36.11 [+ or -] 17.78 Nottingham health profile-fatigue 80.94 [+ or -] 27.37 Nottingham health profile-sleep 50.92 [+ or -] 26.60 Nottingham health profile-social 31.40 [+ or -] 31.40 Nottingham health profile-emotional 44.83 [+ or -] 28.53 Controls Mean [+ or -] SD Patient's global assessment of disease 2.00 [+ or -] 1.56 activity, VAS (cm) Physician's global assessment of disease 1.00 [+ or -] 0.96 activity, VAS (cm) Pain severity, VAS (cm) 2.52 [+ or -] 1.50 Fibromyalgia impact questionnaire-total score 19.32 [+ or -] 9.44 Hamilton anxiety assessment scale total score 8.02 [+ or -] 3.77 Hamilton depression assessment scale total 6.55 [+ or -] 3.44 score Modified fatigue impact scale-total score 20.35 [+ or -] 12.49 Nottingham health profile-pain 16.31 [+ or -] 15.30 Nottingham health profile-physical 12.98 [+ or -] 11.10 Nottingham health profile-fatigue 20.16 [+ or -] 29.37 Nottingham health profile-sleep 13.73 [+ or -] 14.81 Nottingham health profile-social 6.65 [+ or -] 15.02 Nottingham health profile-emotional 9.83 [+ or -] 13.99 P Patient's global assessment of disease <0.001 activity, VAS (cm) Physician's global assessment of disease <0.001 activity, VAS (cm) Pain severity, VAS (cm) <0.001 Fibromyalgia impact questionnaire-total score <0.001 Hamilton anxiety assessment scale total score <0.001 Hamilton depression assessment scale total <0.001 score Modified fatigue impact scale-total score <0.001 Nottingham health profile-pain <0.001 Nottingham health profile-physical <0.001 Nottingham health profile-fatigue <0.001 Nottingham health profile-sleep <0.001 Nottingham health profile-social <0.001 Nottingham health profile-emotional <0.001 p < 0.05; VAS: Visual analog scale. Table 4. Comparison of tumor necrosis factor-alpha, interleukin 1- [beta], interleukin-6, and interleukin-8 expression levels in monocytes of patient and the control groups Patients Mean [+ or -] SD Tumor necrosis factor-alpha 367.04 [+ or -] 130.72 Interleukin 1-beta 459.97 [+ or -] 149.80 Interleukin-6 313.32 [+ or -] 128.98 Interleukin-8 259.67 [+ or -] 165.56 Controls Mean [+ or -] SD P Tumor necrosis factor-alpha 417.40 [+ or -] 143.80 0.065 Interleukin 1-beta 486.70 [+ or -] 167.61 0.394 Interleukin-6 341.80 [+ or -] 158.54 0.312 Interleukin-8 306.95 [+ or -] 181.72 0.170 * p < 0.05 Table 5. Correlation analysis between cytokines and Nottingham health profile subscales NHP-pain NHP-physical NHP-fatigue r p r p r p TNF-[alpha] -0.025 0.839 -0.022 0.857 0.042 0.731 IL-1[beta] 0.78 0.530 0.82 0.506 0.189 0.123 IL-6 0.024 0.846 -0.002 0.985 0.068 0.581 IL-8 -0.030 0.806 -0.031 0.802 0.014 0.913 NHP-sleep NHP-social NHP-emotional r p r p r p TNF-[alpha] 0.252 * 0.038 0.205 0.094 0.239 * 0.049 IL-1[beta] 0.267 * 0.028 0.248 * 0.042 0.317 ** 0.009 IL-6 0.272 * 0.025 0.184 0.133 0.177 0.149 IL-8 0.177 0.149 0.069 0.576 0.099 0.422 NHP: Nottingham health profile; TNF-[alpha]: Tumor necrosis factor-alpha; IL-1[beta]: Interleukin 1-beta; IL-6: Interleukin-6; IL-8: Interleukin-8. * Correlation is significant at the 0.05 level, ** Correlation is significant at the 0.01 level.
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|Title Annotation:||ORIGINAL ARTICLE|
|Author:||Ogut, Evrim; Gur, Ali; Kocyigit, Burhan Fatih; Oztuzcu, Serdar; Cengiz, Beyhan; Altindag, Ozlem; Kar|
|Publication:||Turkish Journal of Rheumatology|
|Date:||Dec 1, 2015|
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