Cytokine biomarkers and chronic pain: association of genes, transcription, and circulating proteins with temporomandibular disorders and widespread palpation tenderness
Gary D Slade, Mathew S Conrad, Luda Diatchenko, Naim U Rashid, Sheng Zhong, Shad Smith, Jesse Rhodes, Alex Medvedev, Sergei Makarov, William Maixner, Andrea G Nackley, Gary D Slade, Mathew S Conrad, Luda Diatchenko, Naim U Rashid, Sheng Zhong, Shad Smith, Jesse Rhodes, Alex Medvedev, Sergei Makarov, William Maixner, Andrea G Nackley
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.
Conflict of interest statement
Statement of conflict of interest. This study includes results from genotyping that was performed using the Algynomics Pain Research Panel. Algynomics Inc. is a company providing research services in personalized pain medication and diagnostics. Five authors have interests in Algynomics Inc. which may be relevant in determining conflicts of interest. Specifically, Drs. Slade, Diatchenko, Smith, Maixner and Nackly hold shares and/or stock options in Algynomics Inc. Also, Drs. Diatchenko and Maixner are Office-holders in Algyonomics Inc. All other authors report no known conflicts of interest.
Published by Elsevier B.V.
Figures
![Fig. 1](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/3221458/bin/nihms328207f1.jpg)
Fig. 2
Circulating cytokine levels are differentially…
Fig. 2
Circulating cytokine levels are differentially associated with log-odds of TMD−WPT and TMD+WPT. (A)…
Fig. 3
TGFβ1 transcription activity is altered…
Fig. 3
TGFβ1 transcription activity is altered among TMD−WPT and TMD+WPT cases. Fold-change in transcription…
Fig. 4
IL-8 and TGFβ1 SNPs interact…
Fig. 4
IL-8 and TGFβ1 SNPs interact to affect log-odds of TMD+WPT. Predicted log-odds of…
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![Fig. 2](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/3221458/bin/nihms328207f2.jpg)
![Fig. 3](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/3221458/bin/nihms328207f3.jpg)
Fig. 4
IL-8 and TGFβ1 SNPs interact…
Fig. 4
IL-8 and TGFβ1 SNPs interact to affect log-odds of TMD+WPT. Predicted log-odds of…
![Fig. 4](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/3221458/bin/nihms328207f4.jpg)
Source: PubMed