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Differential cytokine response in interstitial fluid in skin and serum during experimental inflammation in rats

Tumour necrosis factor‐α (TNF‐α) and interleukin‐1β (IL‐1β) are important mediators produced during inflammation. We hypothesized that the pro‐inflammatory cytokine response in the interstitial fluid (IF) is different from that in serum, and we aimed at quantifying the amount of TNF‐α and IL‐1β in the IF. By centrifugation of rat skin at < 424 g pure IF is extracted. Using ELISA such fluid was analysed for cytokines in back and/or paw skin of pentobarbital‐anaesthetized rats, after either induction of endotoxaemia or ischaemia–reperfusion (I/R) injury. During endotoxaemia, TNF‐α increased in the IF from 0 in control to 640 ± 100 pg ml−1 (mean ±s.e.m.) after 90 min, with the serum concentration being 5–10 times higher at all time points. The response pattern of IL‐1β after lipopolysaccharide (LPS) challenge differed greatly from that of TNF‐α with a large increase in IF from 390 ± 90 to 28 000 ± 1500 pg ml−1 after 210 min, and a significantly smaller increase in serum (600 ± 45 pg ml−1). During reperfusion of the hind paw after 2 h of ischaemia, there was a gradual increase of TNF‐α in both IF of the paw skin and serum after 3 min of reperfusion. Both declined after 20 min. The pattern for IL‐1β differed, increasing significantly less in serum (25 ± 15 pg ml−1 after 20 min of reperfusion) than in the IF (1100 ± 200 pg ml−1). Immunostaining of the inflamed tissues showed increased expression of the two cytokines in cells of both epidermis and dermis compared to controls. Subdermal injections of TNF‐α and IL‐1β at the same concentrations found in IF after LPS infusion affected interstitial fluid pressure significantly. Local TNF‐α production dominates after I/R injury, whereas in endotoxaemia systemic production predominates. For IL‐1β local production dominates in both conditions. Thus, there is a differential pattern of cytokine production and the current method allows the study of the role of cytokines in IF during different inflammatory reactions.