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Regulation of peripheral inflammation by spinal p38 MAP kinase in rats.
- Source :
- PLoS Medicine; Sep2006, Vol. 3 Issue 9, pe338-e338, 1p, 1 Diagram, 2 Charts, 3 Graphs
- Publication Year :
- 2006
-
Abstract
- <bold>Background: </bold>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.<bold>Methods and Findings: </bold>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.<bold>Conclusions: </bold>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. [ABSTRACT FROM AUTHOR]
- Subjects :
- MITOGEN-activated protein kinases
SPINAL cord
CYTOKINES
ARTHRITIS
GENE expression
ARTHRITIS prevention
RNA metabolism
ANIMAL experimentation
BIOLOGICAL models
CELL culture
CELL physiology
COMPARATIVE studies
IMIDAZOLES
SPINAL injections
INTERLEUKIN-1
INTERLEUKINS
JOINTS (Anatomy)
RESEARCH methodology
MEDICAL cooperation
NONSTEROIDAL anti-inflammatory agents
PHOSPHORYLATION
PROTEOLYTIC enzymes
PYRIDINE
RATS
RESEARCH
RESEARCH funding
RHEUMATOID arthritis
SYNOVIAL membranes
T cells
TIME
TRANSFERASES
TUMOR necrosis factors
EVALUATION research
PROTEIN kinase inhibitors
PHARMACODYNAMICS
PREVENTION
Subjects
Details
- Language :
- English
- ISSN :
- 15491277
- Volume :
- 3
- Issue :
- 9
- Database :
- Complementary Index
- Journal :
- PLoS Medicine
- Publication Type :
- Academic Journal
- Accession number :
- 22678071
- Full Text :
- https://doi.org/10.1371/journal.pmed.0030338