Cytokine biomarkers and chronic pain: Association of genes, transcription, and circulating proteins with temporomandibular disorders and widespread palpation tenderness

Center for Neurosensory Disorders, School of Dentistry, University of North Carolina, Chapel Hill, NC 27599-7450, USA.
Pain (Impact Factor: 5.21). 12/2011; 152(12):2802-12. DOI: 10.1016/j.pain.2011.09.005
Source: PubMed


For reasons unknown, temporomandibular disorder (TMD) can manifest as localized pain or in conjunction with widespread pain. We evaluated relationships between cytokines and TMD without or with widespread palpation tenderness (TMD-WPT or TMD+WPT, respectively) at protein, transcription factory activity, and gene levels. Additionally, we evaluated the relationship between cytokines and intermediate phenotypes characteristic of TMD and WPT. In a case-control study of 344 females, blood samples were analyzed for levels of 22 cytokines and activity of 48 transcription factors. Intermediate phenotypes were measured by quantitative sensory testing and questionnaires asking about pain, health, and psychological status. Single nucleotide polymorphisms (SNPs) coding cytokines and transcription factors were genotyped. TMD-WPT cases had elevated protein levels of proinflammatory cytokine monocyte chemotactic protein (MCP-1) and antiinflammatory cytokine interleukin (IL)-1ra, whereas TMD+WPT cases had elevated levels of proinflammatory cytokine IL-8. MCP-1, IL-1ra, and IL-8 were differentially associated with experimental pain, self-rated pain, self-rated health, and psychological phenotypes. TMD-WPT and TMD+WPT cases had inhibited transcription activity of the antiinflammatory cytokine transforming growth factor β1 (TGFβ1). Interactions were observed between TGFβ1 and IL-8 SNPs: an additional copy of the TGFβ1 rs2241719 minor T allele was associated with twice the odds of TMD+WPT among individuals homozygous for the IL-8 rs4073 major A allele, and half the odds of TMD+WPT among individuals heterozygous for rs4073. These results demonstrate how pro- and antiinflammatory cytokines contribute to the pathophysiology of TMD and WPT in genetically susceptible people. Furthermore, they identify MCP-1, IL-1ra, IL-8, and TGFβ1 as potential diagnostic markers and therapeutic targets for pain in patients with TMD.

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Available from: Sergei S. Makarov
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    • "Genetic variants resulting in decreased COMT activity have been associated with chronic pain conditions such as fibromyalgia [24] and TMD [16], which are linked to increased levels of catecholamines [19] [78] and production of proinflammatory molecules [6] [15] [43]. Specifically, patients with fibromyalgia [6] [43] and TMD [20] [39] [66] [67] show higher levels of NO derivatives (eg, nitrite and nitrate) and cytokines such as TNFa, IL-1b, IL-6, and CCL2. "
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    ABSTRACT: Decreased activity of catechol-O-methyltransferase (COMT), an enzyme that metabolizes catecholamines, contributes to pain in humans and animals. Previously, we demonstrated that development of COMT-dependent pain is mediated by both β2-and β3-adrenergic receptors (β2-and β3ARs). Here, we investigated molecules downstream of β2-and β3ARs driving pain in animals with decreased COMT activity. Based on evidence linking their role in pain and synthesis downstream of β2-and β3ARstimulation, we hypothesized that nitric oxide (NO) and pro-inflammatory cytokines drive COMT-dependent pain. To test this, we measured plasma NO derivatives and cytokines in rats receiving the COMT inhibitor OR486 in the presence or absence of the β2AR antagonist ICI118,551+β3AR antagonist SR59230A. We also assessed if the NO synthase inhibitor L-NG-nitroarginine methyl ester (L-NAME) and cytokine neutralizing antibodies block the development of COMT-dependent pain. Results showed that animals receiving OR486 exhibited higher levels of NO derivatives, tumor necrosis factor α (TNFα), interleukin-1β (IL-1β), interleukin-6 (IL-6), and chemokine (C-C motif) ligand 2 (CCL2) in a β2-and β3AR-dependent manner. Additionally, inhibition of NO synthases and neutralization of the innate immunity cytokines TNFα, IL-1β, and IL-6 blocked the development of COMT-dependent pain. Finally, we found that NO influences TNFα, IL-1β, IL-6 and CCL2levels, while TNFα and IL-6 influence NO levels. Altogether, these results demonstrate that β2-and β3ARs contribute to COMT-dependent pain, at least partly, by increasing NO and cytokines. Furthermore, they identify β2-and β3ARs, NO, and pro-inflammatory cytokines as potential therapeutic targets for pain patients with abnormalities in COMT physiology.
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    • "Similarly, elevations of proinflammatory cytokines (e.g., interleukin [IL]-1, IL-6, tumor necrosis factor [TNF]) and chemokines (e.g., RANTES [regulated upon activation , normal T-cell expressed, and secreted]) are evidenced in patients diagnosed with a range of chronic neuropsychiatric disorders including depression (Maes et al. 1995; Levine et al. 1999; Owen et al. 2001; Hestad et al. 2003; Loftis et al. 2008; Howren et al. 2009; Leonard and Maes 2012), anxiety (Hoge et al. 2009; Hou and Baldwin 2012), chronic fatigue syndrome (Arnett and Clark 2012), cancer-related fatigue and cognitive impairment (Meyers et al. 2005), pain disorders (Slade et al. 2011; Alexander et al. 2012), and age-related cognitive decline and dementia (Yaffe et al. 2004; Britschgi and Wyss-Coray 2009; Marksteiner et al. 2011; Corona et al. 2012). Collectively, these studies highlight the impact that immune activation and immune factor dysregulation (both peripherally and centrally) can have on central nervous system (CNS) function. "
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