Journal
BRITISH JOURNAL OF PHARMACOLOGY
Volume 172, Issue 16, Pages 4038-4051Publisher
WILEY-BLACKWELL
DOI: 10.1111/bph.13194
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Funding
- Malcom Feist Cardiovascular Research Endowment, LSU Health Science Center - Shreveport
- Department of Defense [W81XWH-11-1-0577]
- National Institute of General Medical Sciences COBRE Grant [P30-GM110703]
- German Research Foundation (DFG) [BE 5619/1-1]
- MRC [MC_PC_12015] Funding Source: UKRI
- Medical Research Council [MC_PC_12015] Funding Source: researchfish
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Background and PurposeThe 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 ApproachWe 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 x 10(-5)M)], PGE(2) (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 ResultsTonic 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 PGE(2) production in RMLMC.. PGE(2) induced relaxations in RMLMC, comparable to h-IL-1. Conversely, COX-2 and EP4 receptor inhibition reversed relaxation induced by IL-1. Conclusions and ImplicationsThe IL-1-induced decrease in RMLMC tonic contraction was COX-2 dependent, and mediated by PGE(2). 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.
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