Cytokine profile in human skin in response to experimental inflammation, noxious stimulation, and administration of a COX-inhibitor: a microdialysis study.
Animal studies have documented a critical role for cytokines in cell signaling events underlying inflammation and pain associated with tissue injury. While clinical reports indicate an important role of cytokines in inflammatory pain, methodological limitations have made systematic human studies difficult. This study examined the utility of a human in vivo bioassay combining microdialysis with multiplex immunoassay techniques for measuring cytokine arrays in tissue. The first experiment measured cytokines in interstitial fluid collected from non-inflamed and experimentally inflamed skin (UVB). The effects of noxious heat on cytokine release were also assessed. The second experiment examined whether anti-hyperalgesic effects of the COX-inhibitor ibuprofen were associated with decreased tissue levels of the pro-inflammatory cytokines IL-1 beta and IL-6. In the first experiment, inflammation significantly increased IL-1 beta, IL-6, IL-8, IL-10, G-CSF, and MIP-1 beta. Noxious heat but not experimental inflammation significantly increased IL-7 and IL-13. In the second experiment, an oral dose of 400 and 800 mg ibuprofen produced similar anti-hyperalgesic effects suggesting a ceiling effect. Tissue levels of IL-1 beta and IL-6 were not affected after the 400mg dose but decreased significantly (44+/-32% and 38+/-13%) after the 800 mg dose. These results support the utility of explored method for tracking cytokines in human tissue and suggest that anti-hyperalgesic and anti-inflammatory effects of ibuprofen are at least partially dissociated. The data further suggest that high clinical doses of ibuprofen exert anti-inflammatory effects by down-regulating tissue cytokine levels. Explored human bioassay is a promising tool for studying the pathology and pharmacology of inflammatory and chronic pain conditions.
Angst
M S
MS
Department of Anesthesia, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA 94305-5117, USA Department of Anesthesia, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA 94304, USA Department of Anesthesiology, University of Heidelberg, Mannheim, Germany.
Clark
J D
JD
Carvalho
B
B
Tingle
M
M
Schmelz
M
M
Yeomans
D C
DC
D000328:Adult; D015415:Biomarkers / Q000378:metabolism; D018592:Cross-Over Studies; D016861:Cyclooxygenase Inhibitors / Q000008:administration & dosage*; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000378:metabolism; D004311:Double-Blind Method; D005260:Female; D006358:Hot Temperature / Q000009:adverse effects*; D006801:Humans; D018836:Inflammation Mediators / Q000502:physiology*; D008297:Male; D017551:Microdialysis / Q000379:methods*; D010147:Pain Measurement / Q000187:drug effects / Q000379:methods; D012867:Skin / Q000737:chemistry* / Q000187:drug effects / Q000378:metabolism; D013471:Sunburn / Q000188:drug therapy / Q000378:metabolism
D015415:Biomarkers; D016861:Cyclooxygenase Inhibitors; D016207:Cytokines; D018836:Inflammation Mediators