Protective role of the leukotriene B₄receptor BLT2 in murine inflammatory colitis

Abstract

BLT2 is a low-affinity leukotriene B(4) (LTB(4)) receptor that is activated by 12(S)-hydroxyheptadeca-5Z,8E,10E-trienoic acid (12-HHT) and LTB(4). Despite the well-defined proinflammatory roles of BLT1, the in vivo functions of BLT2 remain elusive. To clarify the role of BLT receptors in intestinal inflammation, we assessed susceptibility to dextran sodium sulfate (DSS)-induced colitis in mice lacking either BLT1 or BLT2. BLT2(-/-) mice exhibited increased sensitivity to DSS as compared to wild-type and BLT1(-/-) mice, with more severe body weight loss and inflammation. Expression of inflammatory cytokines such as interferon (IFN)-γ, interleukin (IL)-1β, and IL-6, chemokines such as CXC chemokine ligand 9 (CXCL9) and C-C motif chemokine 19 (CCL19), and metalloproteinases was highly up-regulated in the colons of DSS-treated BLT2(-/-) mice, and there was an enhanced accumulation of activated macrophages. Phosphorylation of the signal transducer and activator of transcription 3 (STAT3) was also markedly accelerated in the crypts of DSS-treated BLT2(-/-) mice. Madin-Darby canine kidney II (MDCKII) cells transfected with BLT2 exhibited enhanced barrier function as measured by transepithelial electrical resistance (TER) and FITC-dextran leakage through MDCK monolayers. Thus, BLT2 is expressed in colon cryptic cells and appears to protect against DSS-induced colitis, possibly by enhancing barrier function in epithelial cells of the colon. These novel results suggest a direct anti-inflammatory role of BLT2 that is distinct from the proinflammatory roles of BLT1.

International Union of Basic and Clinical Pharmacology. LXXXIV: Leukotriene Receptor Nomenclature, Distribution, and Pathophysiological Functions

“…In contrast to the findings of decreased arthritis in BLT 2 R knockout mice, another study demonstrated that this gene disruption induced more severe colitis in response to dextran sodium sulfate (DSS) compared with that in either WT or BLT 1 R knockout mice, which was accompanied by increased expression of inflammatory cytokines, chemokines, and MMPs (Iizuka et al, 2010). However, in the latter study, BLT 2 R deficiency was associated with a dysfunctional barrier function in colonic epithelial cells rather than direct effects on leukocytes (Iizuka et al, 2010). Although the effects of DSS-induced colitis have not been fully explored in BLT 1 R knockout mice, those mice exhibit weight loss similar to that in WT mice, suggesting no protective effects.…”

“…Taken together, these data suggested that although the BLT 1 R may be necessary for the initiation of autoantibody-induced arthritis, BLT 2 R may play a possible role at later stages of disease, when local LTB 4 concentrations are higher in the joint (Mathis et al, 2010). In contrast to the findings of decreased arthritis in BLT 2 R knockout mice, another study demonstrated that this gene disruption induced more severe colitis in response to dextran sodium sulfate (DSS) compared with that in either WT or BLT 1 R knockout mice, which was accompanied by increased expression of inflammatory cytokines, chemokines, and MMPs (Iizuka et al, 2010). However, in the latter study, BLT 2 R deficiency was associated with a dysfunctional barrier function in colonic epithelial cells rather than direct effects on leukocytes (Iizuka et al, 2010).…”

“…Although the effects of DSS-induced colitis have not been fully explored in BLT 1 R knockout mice, those mice exhibit weight loss similar to that in WT mice, suggesting no protective effects. The notion that BLT 2 R agonists other than LTB 4 may be involved in the exacerbated colitis observed after BLT 2 R knockout (Iizuka et al, 2010) is supported by the fact that HHT is produced at 5-to 6-fold higher levels compared with LTB 4 in inflamed colonic biopsy specimens (Zijlstra et al, 1992(Zijlstra et al, , 1993) (see section II.E).…”

“…The tissue distribution of BLT 2 R is different in mouse tissues, with the highest expression in small intestine followed by colon and skin (Iizuka et al, 2005). Physiological and pathophysiological responses associated with BLT 2 R signaling include macrophage and mast cell (MC) chemotaxis Lundeen et al, 2006;Okuno et al, 2008), guinea pig lung parenchyma contraction , and mouse models of angiogenesis , itch-associated scratching (Kim et al, 2008), colitis (Iizuka et al, 2010), and arthritis (Mathis et al, 2010).…”

“…BLT 2 Receptor Knockout. In recent studies, BLT 2 R knockout mice were generated (Iizuka et al, 2010;Mathis et al, 2010). Because of to the close proximity of the BLT 1 R gene promoter, the BLT 2 R gene disruption was generated through insertion into the open reading frame of the BLT 2 gene to avoid alterations of BLT 1 R expression (Iizuka et al, 2010;Mathis et al, 2010).…”