Roles of lipoxin A4 receptor activation and anti-interleukin-1β antibody on the toll-like receptor 2/mycloid differentiation factor 88/nuclear factor-κB pathway in airway inflammation induced by ovalbumin

Abstract

Previous studies investigating the role of toll-like receptors (TLRs) in asthma have been inconclusive. It has remained elusive whether the toll-like receptors (TLR2)/mycloid differentiation factor 88 (MyD88)/nuclear factor (NF)-κB signaling pathway is involved in lipoxin A4 (LXA4)-induced protection against asthma. Therefore, the present study investigated whether ovalbumin (OVA)-induced airway inflammation is mediated by upregulation of the TLR2/MyD88/NF-κB signaling pathway, and whether it proceeds via the inhibition of the activation of the LXA4 receptor and anti-interleukin (IL)-1β antibodies. Mice with airway inflammation induced by OVA administration were treated with or without a LXA4 receptor agonist, BML-111 and anti-IL-1β antibody. Serum levels of IL-1β, IL-4, IL-8 and interferon-γ (IFN-γ) were assessed, and levels of IL-1β, IL-4, IL-8 and OVA-immunoglobulin (Ig)E, as well as leukocyte counts in the bronchoalveolar lavage fluid (BALF) were measured. Pathological features and expression of TLR2, MyD88 and NF-κB in the lungs were analyzed. Expression of TLR2 and MyD88, and activation of NF-κB in leukocytes as well as levels of IL-4, IL-6 and IL-8 released from leukocytes exposed to IL-1β were assessed. OVA treatment increased the levels of IL-1β, IL-4 and IL-8 in the serum and BLAF, the number of leukocytes and the levels of OVA-IgE in the BALF, the expression of TLR2 and MyD88, and the activation of NF-κB in the lung. These increments induced by OVA were inhibited by treatment with BML-111 and anti-IL-1β antibodies. Treatment of the leukocytes with BML-111 or TLR2 antibody, or MyD88 or NF-κB inhibitor, all blocked the IL-1β-triggered production of IL-4, IL-6 and IL-8 and activation of NF-κB. Treatment of the leukocytes with BML-111 or TLR2 antibody suppressed IL-1β-induced TLR2 and MyD88 expression. The present study therefore suggested that OVA-induced airway inflammation is mediated by the TLR2/MyD88/NF-κB pathway. IL-1β has a pivotal role in the airway inflammation and upregulation of the TLR2/MyD88/NF-κB pathway induced by OVA. BML-111 and anti-IL-1β antibody restrains the OVA-induced airway inflammation via downregulation of the TLR2/MyD88/NF-κB pathway.

The Lipoxin Receptor/FPR2 Agonist BML-111 Protects Mouse Skin Against Ultraviolet B Radiation

“…Keratinocytes and macrophages are the main source of these NF-κB-dependent cytokines upon UVB radiation [39,40], which are released to control inflammatory response [41]. In a model of ovalbumin-induced asthma, treatment with BML-111 reduces NF-κB activation and the upstream adaptor molecule myeloid differentiation primary response 88 (MyD88) in the lungs and recruited immune cells [42]. Corroborating that data, in a model of psoriasis induced by IMQ, treatment with BML-111 reduced NF-κB activation and other clinical signs such as epidermal erythema, scaling, and thickening of the dorsal skin [22].…”

“…Considering that neutrophils and mast cells express the ALX/FPR2 receptor [14,15], it is also possible that BML-111 directly inhibited the chemoattraction of these cells. In fact, at least for neutrophils, it was shown that LXA4 and BML-111 reduce their chemoattraction [13,14,16,20,42,43].…”

BML-111 Reduces Neuroinflammation and Cognitive Impairment in Mice With Sepsis via the SIRT1/NF-κB Signaling Pathway

“…However, native LXA4 is rapidly biosynthesized and inactivated, and so it is necessary to synthesize stable and powerful analogs ( Chiang et al, 2000 ). BML-111, 5(S), 6(R), 7-trihydroxyheptanoic acid methyl ester, is a synthetic ALX agonist, which reportedly inhibits neutrophil recruitment and peripheral inflammation ( Lee et al, 1991 ; Gong J. et al, 2012 ; Li et al, 2013 ; Kong et al, 2015 ). It has been demonstrated that BML-111 exerts anti-inflammatory effects in the cerebral cortex and maintains the integrity of the blood–brain barrier after ischemic stroke ( Hawkins et al, 2014 ).…”

Pilot application of lipoxin A4 analog and lipoxin A4 receptor agonist in asthmatic children with acute episodes

“…A solution of BML-111 (2 mg/0.5 ml 100% alcohol) was diluted in 2 ml normal saline as an inhalation solution for each patient in the relevant group. Previous studies were used as references for the selection of 5(S),6(R)-LXA 4 methyl ester and BML-111 dosages (17,(28)(29). Pulmicort, an inhaled glucocorticoid budesonide, was obtained from AstraZeneca (London, UK).…”

“…A previous study indicated that treatment of allergic eczema in infants with topical 15(R/S)-methyl-LXA 4 decreased eczema severity and duration, and improved patients' quality of life with a similar efficacy to topical corticosteroids (27). LXA 4 exhibits the potential to be a novel therapeutic treatment in asthma (5,28,29). Thus, clinical trials with LXA 4 stable analogs are required to determine its efficacy and safety in the treatment of asthmatic patients.…”