IL-1 reduces tonic contraction of mesenteric lymphatic muscle cells, with the involvement of cycloxygenase-2 and prostaglandin E2.
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BACKGROUND AND PURPOSE: The lymphatic system maintains tissue homeostasis by unidirectional lymph flow, maintained by tonic and phasic contractions within subunits, 'lymphangions'. Here we have studied the effects of the inflammatory cytokine IL-1 on tonic contraction of rat mesenteric lymphatic muscle cells (RMLMC). EXPERIMENTAL APPROACH: We measured IL-1 in colon-conditioned media (CM) from acute (AC-CM, dextran sodium sulfate) and chronic (CC-CM, T-cell transfer) colitis-induced mice and corresponding controls (Con-AC/CC-CM). We examined tonic contractility of RMLMC in response to CM, the cytokines h-IL-1 or h-TNF- (5, 10, 20ngmL(-1) ), with or without COX inhibitors [TFAP (10(-5) M), diclofenac (0.2 10(-5) M)], PGE2 (10(-5) M)], IL-1-receptor antagonist, Anakinra (5gmL(-1) ), or a selective prostanoid EP4 receptor antagonist, GW627368X (10(-6) and 10(-7) M). KEY RESULTS: Tonic contractility of RMLMC was reduced by AC- and CC-CM compared with corresponding control culture media, Con-AC/CC-CM. IL-1 or TNF- was not found in Con-AC/CC-CM, but detected in AC- and CC-CM. h-IL-1 concentration-dependently decreased RMLMC contractility, whereas h-TNF- showed no effect. Anakinra blocked h-IL-1-induced RMLMC relaxation, and with AC-CM, restored contractility to RMLMC. IL-1 increased COX-2 protein and PGE2 production in RMLMC.. PGE2 induced relaxations in RMLMC, comparable to h-IL-1. Conversely, COX-2 and EP4 receptor inhibition reversed relaxation induced by IL-1. CONCLUSIONS AND IMPLICATIONS: The IL-1-induced decrease in RMLMC tonic contraction was COX-2 dependent, and mediated by PGE2 . In experimental colitis, IL-1 and tonic lymphatic contractility were causally related, as this cytokine was critical for the relaxation induced by AC-CM and pharmacological blockade of IL-1 restored tonic contraction.