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

Slade, Gary D.a; Conrad, Mathew S.a; Diatchenko, Ludaa; Rashid, Naim U.b; Zhong, Shenga; Smith, Shada; Rhodes, Jessea; Medvedev, Alexb; Makarov, Sergeic; Maixner, Williama; Nackley, Andrea G.a,*

Section Editor(s):

doi: 10.1016/j.pain.2011.09.005

Summary Women with widespread vs localized chronic pain exhibit distinctive alterations in molecular-genetic profiles of the inflammatory mediators MCP-1, IL-1ra, IL-8, and TGFβ1.

ABSTRACT 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.

Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

aCenter for Neurosensory Disorders, School of Dentistry, University of North Carolina, Chapel Hill, NC 27599, USA

bDepartment of Biostatistics, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC 27599, USA

cAttagene, Inc, Morrisville, NC 27560, USA

*Corresponding author. Address: Center for Neurosensory Disorders, School of Dentistry, CB 7450, University of North Carolina, Chapel Hill, NC 27599-7450, USA. Tel.: +1 919 966 5083; fax: +1 919 966 5339.



Submitted August 8, 2011; revised August 29, 2011; accepted September 8, 2011.

© 2011 Lippincott Williams & Wilkins, Inc.
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