Long Term Immune-Mediated Inflammation and Pain in a TNFR (P55/P75-/-) Dual Deficient Murine Model (original) (raw)

Gastroenterology, 2011

Abstract

ABSTRACT Long Term Immune-Mediated Inflammation and Pain in a TNFR (P55/P75-/-) Dual Deficient Murine Model Karin N. Westlund, Liping Zhang, Helieh S. Oz Dysregulated TNF contributes to numerous pathophysiological conditions including IBD and arthritis. However, the functional involvement of p55 and p75 TNFalpha receptors in IBD is not fully discovered. Mustard oil (MO, allylisothiocyanate) is a potent TRPA1 ion channel neuronal activator that promotes allodynia and hyperalgesia. We hypothesized that, MO application to provoke inflammation in mice with genetic ablation in p55/p75 will manifest with a rapid, and transient colitic response associated with a neuronal damage and sensitization. Methods: Mice dually deficient in p55 and p75 and their background B6129SF2/J strain were used. Monoarthritis was induced with complete Freund's adjuvant injected directly into knee joint cavity for weekly behavioral monitoring. Following recovery, animals were subjected to second colonic MO inflammatory insult. Pain-related behavior was monitored for >12 weeks. Analysis of cytokines and chemokines immune profile was defined using the Proteomic Profiler Panel Array. Results: Animals developed immediate lowered thermal and mechanical thresholds on their footpads 30min following colonic MO stimulation that persisted for 2 weeks in wildtype animals. TNFR p55/p75-/- deficient animals remained secondary hyperalgesic (decreased paw withdrawal and mechanical threshold) and reactivated a chronic spontaneous pain symptoms related postures in the injected leg (hypertonic guarding and partial weight bearing) that lasted >12 weeks. Significant differences were noted in cytokine/chemokine profiles including TNFalpha, RANTES, IL-2, and INFgamma family cytokines. Conclusions: In this study we devised a long term (>12 weeks) neuronal hypersensitivity with immune-mediated inflammatory response. These data imply that impaired binding and signaling TNF pathways, and loss of the two protective soluble p55 sTNF-R and p75 sTNF-R inhibitory factors in these genetically impaired mouse model (p55 TNF-R and p75 TNF-R dual deficient) play a pivotal role in the pathogenesis of chronic inflammatory responses. Supporting grant NIHNS3904(KNW), and NIHDE19177(HO)

Helieh Oz hasn't uploaded this paper.

Let Helieh know you want this paper to be uploaded.

Ask for this paper to be uploaded.