Involvement of cytokines in lipopolysaccharide-induced facilitation of CGRP release from capsaicin-sensitive nerves in the trachea: studies with interleukin-1beta and tumor necrosis factor-alpha.
Lipopolysaccharide (LPS), an endotoxin, produces pain behavior, inflammation, and changes in immune function. Many of these effects are secondary to the production of cytokines. In the present study, we investigated the effect of LPS on the releasing function of afferent terminals as measured by calcitonin gene-related peptide (CGRP) release in ex vivo perfused rat trachea, and examined the possible role of the cytokines interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) as intermediaries in this effect. Systemic injection of LPS (0.75 mg/kg, i.p.) in adult rats induced an increase in body temperature followed by hypothermia, indicating ongoing infection. We observed that capsaicin-induced (0.1 microM) tracheal CGRP release was significantly enhanced in the LPS-treated animals after 5 hr. This enhancement of the peptide release by LPS was blocked by IL-1beta tripeptide antagonist Lys-D-Pro-Thr (10 microM) and mimicked by IL-1beta and TNF-alpha (10-100 pg/ml), suggesting that the potentiating effect of LPS on CGRP release is mediated by generation of IL-1beta and TNF-alpha. IL-1beta-induced augmentation of CGRP release was blocked by Lys-D-Pro-Thr. Additionally, the cyclooxygenase inhibitor ketorolac (10 microM) significantly attenuated the facilitatory effects of LPS and IL-1b, indicating involvement of prostanoids. These findings suggest that endotoxin treatment generated cytokines such as IL-1b and TNF-alpha that regulated the peripheral releasing function of primary sensory afferents by sensitizing the terminals and facilitating peptide release. This effect is prostanoid dependent.
Hua
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Department of Anesthesiology, University of California, San Diego, La Jolla 92093-0818, USA.
Chen
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Fox
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Myers
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D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism*; D002211:Capsaicin / Q000494:pharmacology; D016207:Cytokines / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D007375:Interleukin-1 / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D014132:Trachea / Q000187:drug effects*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D016207:Cytokines; D007375:Interleukin-1; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D015740:Calcitonin Gene-Related Peptide; D002211:Capsaicin