Enhanced cytokine mRNA levels in attack-free patients with familial Mediterranean fever

Abstract

Familial Mediterranean fever (FMF) is a recessively inherited inflammatory disorder, characterized by recurrent attacks of fever and serositis. Screening of mutations in the causing gene (MEFV) now allows accurate diagnosis of FMF among other inflammatory conditions. It is well documented that secreted levels of some pro-inflammatory cytokinesFamilial Mediterranean fever (FMF) is the prototype of a group of hereditary inflammatory disorders. Patients experience short, self resolving, attacks of fever and serosal inflammation (peritonitis, arthritis, pleuritis). 1 Although between attacks patients totally recover clinically, biological markers of inflammation (Serum Amyloid A protein, C Reactive Protein) sometimes remain elevated. 2,3 The gene for this recessive disorder (MEFV) was identified 4 years ago by a positional cloning strategy. 4,5 Screening for MEFV mutations has provided the first specific tool for diagnosing FMF, which can now be differentiated from the various other inflammatory conditions. However, it has been proposed that some MEFV variants may predispose to inflammation in general, [6][7][8] and indeed, preferential association with other inflammatory conditions has been reported. [9][10][11] The function of MEFV is still unknown. The disease phenotype and the almost exclusive expression of MEFV in leukocytes suggest that the corresponding protein plays an important role in the inflammatory cascade. [12][13][14] Some inflammatory mediators such as cytokines have been shown to be involved in the pathogenesis of FMF. [15][16][17][18] The cytokine network has been studied in many circumstances in clinically diagnosed patients, ie during and between attacks, both on and off colchicine treatment, and after ex vivo induction, as well as in controls. The secreted levels of pro-inflammatory cytokines are enhanced during attacks, whereas during attack-free periods they do not differ or are slightly higher than in healthy subjects.The present study is the first investigation of cytokines (i) at the transcriptional level, and (ii) in genetically ascertained patients. We have compared messenger RNA (mRNA) levels of four pro-inflammatory cytokines, tumor necrosis factor alpha (TNF-␣), interleukin 1 beta (IL-1␤), interleukin 6 (IL-6) and interleukin 8 (IL-8) in FMF patients in clinical remission and in healthy controls. TNF-␣ plays a key role in the inflammatory process by stimulating production of IL-1, which has a pyretic action; IL-6, promotes the release of acute phase reactants, and IL-8, is a chemoattractant.The FMF group comprised 44 patients, whose composition is shown in Table 1. 19 They were all in attack-free intervals upon blood sampling, based on clinical criteria: (i) no fever, no pain, no sign of inflammation, (ii) the time of their last attack was systematically documented, and happened at least 3 weeks earlier. The control group comprised 31 mutation-free healthy volunteers, unrelated to the patient group. We set up a multiplex RT-PCR strategy to quantify the cytokine mRNA levels relative to ...

Familial Mediterranean Fever

“…IL-6 and IL-8 are also increased during episode-free period. Although their levels are decreased under the treatment with colchicine, the transcription rates remain unchanged (54,(62)(63). In addition, IL-10, IL-12, IL-17 and IL-18 were also reported to increase during episode-free period.…”

Glutathione-S-Transferase Variants are not Associated With Increased Carotid Intima-Media Thickness in Turkish Familial Mediterranean Fever Patients

“…30 Moreover, attack-free periods of FMF are characterized by subclinical inflammation. 10,11 It was shown that serum IL-17 and IL-18 levels of FMF patients are higher than healthy controls both during acute phase and attack-free period.…”

“…Although the nature of this regulation is not revealed precisely, pyrin, within a complex called inflammasome, serves as a regulator of the conversion of pro-interleukin (IL)-1b to mature IL-1b. 6,7 During inflammation episodes, neutrophils migrate into serous cavities and the levels of acutephase inflammatory products, including serum amyloid A and C reactive protein, 8 and cytokines including IL-6, 9,10 IL-8, 10 IL-17 11 and IL-18 11,12 increase. Besides these findings, it has been reported that substantial subclinical inflammation occurs during attack-free periods in patients with FMF and oxidative stress and oxidant/antioxidant imbalance might play a role in this persistent subclinical inflammation.…”

“…Besides these findings, it has been reported that substantial subclinical inflammation occurs during attack-free periods in patients with FMF and oxidative stress and oxidant/antioxidant imbalance might play a role in this persistent subclinical inflammation. [8][9][10][11][12] The relationship between inflammation and atherosclerosis has been investigated in several studies in chronic inflammatory diseases such as inflammatory bowel disease 13 and coeliac disease. 14 Chronic inflammation and immune dysregulation play a major role in both initiation and the development of atherosclerosis.…”

Ailevi ASkdeniz Ateşi (FMF) Hastalığında Akut Faz Yanıtı İle Tümör Nekrozis Faktör- İnterlökin-8 ve İnterlökin-6 Düzeylerinin Değerlendirilmesi

“…Buna karşın 1997'de yayınlanan bir başka çalışmada İL-6 ve İL-8 düzeylerinin FMF hastalarında atak dö-nemlerinde ataksız döneme göre yüksek olduğu bulunmuştur fakat istatiksel fark saptanmamıştır (23). İlginç olarak çok kısa süre önce yayınlanan bir çalışmada ise FMF hastalarının atak dışı dö-nemlerinde bakılan İL-1b, İL-6 ve İL-8 düzeyleri-nin sağlıklı kontrollerden yüksek olduğu saptanmış ve bunun da FMF hastalarında olduğu düşü-nülen subklinik inflamasyonun kanıtı olduğu belirtilmiştir (24).…”