Differential expression patterns of cytokines in complex regional pain syndrome

Abstract

Complex regional pain syndromes (CRPS) are characterized by persistent and severe pain after trauma or surgery. Neuro-immune alterations are assumed to play a pathophysiological role. Here we set out to investigate whether patients with CRPS have altered systemic pro- and anti-inflammatory cytokine profiles compared to controls on mRNA and protein level. We studied blood cytokine mRNA and protein levels of the pro-inflammatory cytokines tumor necrosis factor-alpha (TNF), interleukin-2 (IL-2) and IL-8 and the anti-inflammatory cytokines IL-4, IL-10, and transforming growth factor-beta1 (TGF beta 1) in 40 prospectively recruited patients with CRPS I, two patients with CRPS II, and 34 controls. Quantitative real-time PCR and enzyme linked immunosorbent assay were used. Additionally, the patients underwent quantitative sensory testing and were assessed with the McGill pain questionnaire and the Hospital anxiety and depression scale. Patients with CRPS had higher blood TNF and IL-2 mRNA levels (p=0.005; p=0.04) and lower IL-8 mRNA levels (p<0.001) than controls. The mRNA for the anti-inflammatory cytokines IL-4 and IL-10 was reduced in the patient group (p=0.004; p=0.006), whereas TGF beta 1 mRNA levels did not differ between groups. These results were paralleled by serum protein levels, except for TGF beta 1, which was reduced in patients with CRPS, and for IL-8, which gave similar protein values in both groups. Sensory testing showed a predominant loss of small fiber-related modalities in the patient group. The shift towards a pro-inflammatory cytokine profile in patients with CRPS suggests a potential pathogenic role in the generation of pain.

IL-4, JAK-STAT signaling, and pain

“…In patients with complex regional pain syndromes, TNF-α and IL-2 serum levels were higher and IL-4, IL-10, and TGF-β levels were lower than in the controls. 81 In another patients cohort with chronic widespread pain including fibromyalgia, serum levels of IL-4 and IL-10 were also lower than in healthy controls but no significant differences were observed between the plasma levels of IL-2, IL-8, TNF-α, or TGF-β of patients and controls. 82 In those two patient groups, a relative elevation of the ratio of pro-to anti-inflammatory cytokines seems to coincide with pain.…”

The inflammasome as a target for pain therapy

“…7 95 Clinical studies have demonstrated elevated IL-1b concentrations in the skin of CRPS patients. 97 Thus, peripheral IL-1b production controlled by the NALP1 inflammasome may support pain in the CRPS model. During neurogenic inflammation, peripheral afferent and efferent neurons induce a rapid release of neural mediators independent of those produced by immune cells.…”

Immune dysfunction and chronic inflammation following spinal cord injury

“…Individuals diagnosed with major depression have been consistently reported to demonstrate elevated levels of proinflammatory cytokines, 45,46 and those with neuropathic pain have been shown to have altered levels of inflammatory mediators with elevations in the proinflammatory cytokines TNF, IL-6 and IL-2 along with reductions in anti-inflammatory cytokines such as IL-10 and IL-4. 1, 47 As these disorders have a highly elevated prevalence following SCI, they too may contribute to the elevated inflammatory status observed in this population. The prevalence of depression following SCI is estimated to be five times greater in comparison with the general population with rates of 20-40%.…”