Lipoxin A4 and Aspirin-Triggered 15-Epi-Lipoxin A4 Antagonize TNF-α-Stimulated Neutrophil-Enterocyte Interactions In Vitro and Attenuate TNF-α-Induced Chemokine Release and Colonocyte Apoptosis in Human Intestinal Mucosa Ex Vivo

Abstract

Lipoxins (LXs) are lipoxygenase-derived eicosanoids and putative endogenous braking signals for inflammation in the gastrointestinal tract and other organs. Aspirin triggers the production of 15-epimers during cell-cell interaction in a cytokine-primed milieu, and aspirin-triggered 15-epi-5(S),6(R),15(S)-trihydroxy-7,9,13-trans-11-cis-eicosatetraenoic acid (15-epi-LXA4) may contribute to the bioactivity profile of this prototype nonsteroidal anti-inflammatory drug in vivo. We determined the effect of LXA4, 15-(R/S)-methyl-11,12-dehydro-LXA4 methyl ester (15-(R/S)-methyl-LXA4), and stable analogs of LXA4 on TNF-α-stimulated neutrophil-enterocyte interaction in vitro and TNF-α-stimulated chemokine release, changes in mucosal architecture, and enterocyte apoptosis in cytokine-activated intact human colonic mucosa ex vivo. LXA4, 15-(R/S)-epi-LXA4, and 16-phenoxy-11,12-dehydro-17,18,19,20-tetranor-LXA4 methyl ester (16-phenoxy-LXA4) inhibited TNF-α-stimulated neutrophil adherence to epithelial monolayers at nanomolar concentrations. In parallel experiments involving human colonic mucosa ex vivo, LXA4potently attenuated TNF-α-stimulated release of the C-X-C chemokine IL-8, and the C-C chemokines monocyte-chemoattractant protein-1 (MCP-1) and RANTES. Exposure of strips of normal human colonic mucosa to TNF-α induced disruption of mucosa architecture and enhanced colonocyte apoptosis via a caspase-3-independent mechanism. Prior exposure of the mucosa strips to 15-(R/S)-methyl-LXA4 attenuated TNF-α-stimulated colonocyte apoptosis and protected the mucosa against TNF-α-induced mucosal damage. In aggregate, our data demonstrate that lipoxins and aspirin-triggered 15-epi-LXA4 are potent antagonists of TNF-α-mediated neutrophil-enterocyte interactions in vitro, attenuate TNF-α-triggered chemokine release and colonocyte apoptosis, and are protective against TNF-α-induced morphological disruption in human colonic strips ex vivo. Our observations further expand the anti-inflammatory profile of these lipoxygenase-derived eicosanoids and suggest new therapeutic approaches for the treatment of inflammatory bowel disease.

Lipoxin A4 inhibits immune cell binding to salivary epithelium and vascular endothelium

“…These studies confirm the role of proinflammatory cytokines in immune cell adherence in salivary epithelium and provide the first evidence for direct antiinflammatory effects of LXA 4 in salivary epithelium. Previous studies in intestinal epithelial cell lines and colonic epithelium indicated that LXA 4 and its stable analogs downregulate chemokine secretion (38). LXA 4 also enhanced mucosal antimicrobial protection by stimulating the expression of the bactericidal/permeability-increasing protein (BPI) in oral and intestinal epithelial cells (14), and accelerated epithelial wound closure in murine cornea (40).…”

Molecular Mechanisms of Topical Anti-Inflammatory Effects of Lipoxin A4in Endotoxin-Induced Uveitis

“…It is noteworthy that several recent studies have suggested that LXA 4 opposes the inflammatory property of TNF-␣ and IL-1␤. Indeed, LXA 4 inhibits IL-1␤-induced release of IL-6, IL-8, and matrix metalloproteinase-3 in fibroblast-like synoviocytes, antagonizes TNF-␣-initiated IL-1␤ production by neutrophils Sodin-Semrl et al, 2000) and attenuates TNF-␣-stimulated IL-8 and monocyte chemoattractant protein-1 release by colonic cell lines (Gronert et al, 1998;Goh et al, 2001). Moreover, LXA 4 stable analogs are able to inhibit the renal synthesis of IL-1␤ in experimental ischemic renal injury (Leonard et al, 2002;Kieran et al, 2003;Wu et al, 2005) and to block the extracellular signal-regulated kinase-dependent TNF-␣ secretion from human T cells (Ariel et al, 2003).…”

Reduction of Renal Ischemia-Reperfusion Injury in 5-Lipoxygenase Knockout Mice and by the 5-Lipoxygenase Inhibitor Zileuton

“…Lipoxin-A 4 (or its analogs) reduces the degree of inflammation (Takano et al, 1997;Goh mice. ICAM-1 expression; sham-operated group (A), wild-type group subjected to renal I/R (B), zileuton treated group subjected to renal I/R (C), and 5-LOX Ϫ/Ϫ mice group subjected to renal I/R (D).…”