Nuclear factor kappa B regulated monocyte chemoattractant protein-1/chemokine CC motif receptor-2 expressing in spinal cord contributes to the maintenance of cancer-induced bone pain in rats

• Published in: Molecular pain Vol. 14; p. 1744806918788681
• Main Authors: Wang, Yungong, Ni, Huadong, Li, Hongbo, Deng, Houshen, Xu, Long S, Xu, Shijie, Zhen, Ying, Shen, Hui, Pan, Huan, Yao, Ming
• Format: Journal Article
• Language: English
• Published: Los Angeles, CA SAGE Publications 01.01.2018; Sage Publications Ltd
• Subjects: Animals; Antibodies - therapeutic use; Benzoxazines - therapeutic use; Bone cancer; Bone Neoplasms - complications; Bone Neoplasms - diagnostic imaging; Cancer Pain - diagnostic imaging; Cancer Pain - etiology; Cancer Pain - pathology; CC chemokine receptors; CCR2 protein; Cell Line, Tumor; Chemokine CCL2 - immunology; Chemokine CCL2 - metabolism; Chemokines; Cytokines - metabolism; Disease Models, Animal; Female; Inflammation; Inoculation; Interleukin 4; Microglia; Monocyte chemoattractant protein; Monocyte chemoattractant protein 1; Monocytes; NF-kappa B - metabolism; NF-κB protein; Nitriles - therapeutic use; Pain; Pain perception; Pain Threshold - drug effects; Phosphopyruvate Hydratase - metabolism; Polymerase chain reaction; Rats; Rats, Sprague-Dawley; Receptors, CCR2 - metabolism; Reverse transcription; Signal transduction; Spinal cord; Spinal Cord - metabolism; Spiro Compounds - therapeutic use; Sulfones - therapeutic use; Tibia; Time Factors; Tumor necrosis factor-α; Up-Regulation - drug effects; γ-Interferon; Cancer-induced bone pain; MCP-1/CCR2 axis; astrocytes; chemokines; neurons; NF-κB signaling pathway
• ISSN: 1744-8069; 1744-8069
• DOI: 10.1177/1744806918788681

Background: Chemokine, monocyte chemoattractant protein-1 (MCP-1), is a potential factor to cause cancer-induced bone pain (CIBP). NF-κB signaling is very important in mediating the expression of chemokines and may have a role in CIBP. However, the mechanism is still unclear. This study investigates the role of NF-κB in CIBP by regulating MCP-1/chemokine CC motif receptor-2 (CCR2) signaling pathway. Methods: A rat CIBP model was established by injecting Walker-256 cells into the tibia medullary cavity. Nine days later, animals were intrathecally administrated with MCP-1 neutralizing antibody, CCR2 antagonist (RS504393), or NF-кB inhibitor (BAY11–7081). Mechanical paw withdrawal threshold was used to assess pain behavior and sciatic functional index, and radiographic images were adopted to evaluate the damage of nerve and bone. The spinal cords were harvested for Western blot and quantitative reverse transcription polymerase chain reaction. The distribution of MCP-1, CCR2, and NF-кB was detected by double immunofluorescent staining. Results: CIBP caused remarkable bone destruction, injury of sciatic and femoral nerve, and persistent (>15 days) mechanical allodynia in rats. Tumor cell inoculation upregulate MCP-1 and NF-кB in activated neurons as well as CCR2 in neurons and microglia of the spinal cord. MCP-1 antibody, RS504393, and BAY11–7081 partially reversed CIBP-induced mechanical allodynia, and CIBP regulated the expression levels of pro-inflammatory cytokines, tumor necrosis factor-α and interferon-γ, and anti-inflammatory cytokine, interleukin 4, and BAY11–7081 lowered CIBP-induced MCP-1 and CCR2 expressions in a dose-dependent manner. Conclusion: In conclusion, NF-кB signaling pathway regulates the expressions of MCP-1/CCR2-induced inflammatory factors in the spinal cord of CIBP rats.