Regulation of peripheral inflammation by spinal p38 MAP kinase in rats

• Published in: PLoS medicine 2006-09, Vol.3 (9), p.e338-e338
• Main Authors: Boyle, David L, Jones, Toni L, Hammaker, Deepa, Svensson, Camille I, Rosengren, Sanna, Albani, Salvatore, Sorkin, Linda, Firestein, Gary S
• Format: Article
• Language: English
• Subjects: Allergy/Immunology; Animals; Anti-Inflammatory Agents, Non-Steroidal - administration & dosage; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Arthritis; Arthritis, Experimental - metabolism; Arthritis, Experimental - pathology; Arthritis, Experimental - prevention & control; Arthritis, Rheumatoid - metabolism; Arthritis, Rheumatoid - pathology; Arthritis, Rheumatoid - prevention & control; Autoimmune Diseases; Cell Biology; Cell Proliferation - drug effects; Cells, Cultured; Central nervous system; Disease Models, Animal; Drug dosages; Drugs and Adverse Drug Reactions; Encyclopedias; Gene expression; Health aspects; Imidazoles - administration & dosage; Imidazoles - pharmacology; Immunology; Inflammation; Injections, Spinal; Interleukin-1 - metabolism; Interleukin-6 - metabolism; Joints - drug effects; Joints - pathology; Kinases; Matrix Metalloproteinase 3 - metabolism; Nervous system; Nociceptors; p38 Mitogen-Activated Protein Kinases - antagonists & inhibitors; p38 Mitogen-Activated Protein Kinases - metabolism; Pain; Pharmacology/Drug Discovery; Phosphorylation; Protein Kinase Inhibitors - administration & dosage; Protein Kinase Inhibitors - pharmacology; Proteins; Pyridines - administration & dosage; Pyridines - pharmacology; Rats; Rats, Inbred Lew; Rheumatoid Arthritis; Rheumatology; RNA, Messenger - metabolism; Skin diseases; Spinal cord; Spinal Cord - drug effects; Spinal Cord - enzymology; Synovial Membrane - drug effects; Synovial Membrane - metabolism; Synovial Membrane - pathology; T-Lymphocytes - drug effects; Time Factors; TNF inhibitors; Tumor Necrosis Factor-alpha - metabolism; Tumor necrosis factor-TNF
• ISSN: 1549-1676; 1549-1277; 1549-1676
• DOI: 10.1371/journal.pmed.0030338

Somatic afferent input to the spinal cord from a peripheral inflammatory site can modulate the peripheral response. However, the intracellular signaling mechanisms in the spinal cord that regulate this linkage have not been defined. Previous studies suggest spinal cord p38 mitogen-activated protein (MAP) kinase and cytokines participate in nociceptive behavior. We therefore determined whether these pathways also regulate peripheral inflammation in rat adjuvant arthritis, which is a model of rheumatoid arthritis. Selective blockade of spinal cord p38 MAP kinase by administering the p38 inhibitor SB203580 via intrathecal (IT) catheters in rats with adjuvant arthritis markedly suppressed paw swelling, inhibited synovial inflammation, and decreased radiographic evidence of joint destruction. The same dose of SB203580 delivered systemically had no effect, indicating that the effect was mediated by local concentrations in the neural compartment. Evaluation of articular gene expression by quantitative real-time PCR showed that spinal p38 inhibition markedly decreased synovial interleukin-1 and -6 and matrix metalloproteinase (MMP3) gene expression. Activation of p38 required tumor necrosis factor alpha (TNFalpha) in the nervous system because IT etanercept (a TNF inhibitor) given during adjuvant arthritis blocked spinal p38 phosphorylation and reduced clinical signs of adjuvant arthritis. These data suggest that peripheral inflammation is sensed by the central nervous system (CNS), which subsequently activates stress-induced kinases in the spinal cord via a TNFalpha-dependent mechanism. Intracellular p38 MAP kinase signaling processes this information and profoundly modulates somatic inflammatory responses. Characterization of this mechanism could have clinical and basic research implications by supporting development of new treatments for arthritis and clarifying how the CNS regulates peripheral immune responses.