**4. Experimental evidence for cytokine/chemokine pathogenesis**


Three integrated reviews, although acknowledging discrepancies in the literature, attempted to associate cytokine abnormalities with core FMS symptoms [26–28]. The first concluded, "There are discrepant findings related to whether pro-inflammatory and anti-inflammatory cytokines are elevated or reduced in persons with FMS and whether they correlate with core symptoms." [26]. The second [27] critiqued one of the more persuasive analysis, "….. may have cytokine driven abnormalities to explain their pain…IL-1ra and IL-6 were significantly higher after stimulating PBMC of FMS patients compared to controls [29]." The results of this study were not corroborated in a second study [24].

The third review of 12 separate analyses reported increased inflammatory cytokines IL-1ra, IL-6, and IL-8, and anti-inflammatory interleukin-10 (IL-10) or low anti-inflammatory interleukin-4 (IL-4) and IL-10 [24]. Among the inflammatory chemokines also linked to signs and symptoms, monocyte chemoattractant protein-1 (MCP-1), eotaxin among others, were elevated.

Two potentially innovative separate controlled analyses described cytokine and chemokine concentrations in the supernatant after mitogen stimulation of cultured monocytes, using a logistical regression model to achieve statistically determined weighting for each chemokine and cytokine, and offered this score as diagnostic test for FMS [30, 31]. Of interest, the inflammatory cytokines and chemokines including IL-6 were lower in concentration compared to healthy controls or individuals with autoimmune disease. These findings suggest increased damping control of inflammation in FMS. The authors of both these studies, however, failed to determine the prevalence of depression or analyze its potential effects on cytokine concentrations.

Among the most novel analyses was a report of elevation of intrathecal IL-8 derived from glia cells supporting the hypothesis that FMS symptoms might be mediated by glial cell activation through sympathetic nervous system mechanisms [32].

In summary, in individuals with FMS, peripheral blood IL-6, IL-1ra, and IL-8 concentrations may be a bit higher and IL-4 and IL-10 lower, and IL-8 may be relatively higher in the cerebral spinal fluid than in healthy controls. Inflammatory chemokines may also be higher than in healthy control patients.
