ABSTRACT
ETHNOPHARMACOLOGICAL RELEVANCE: Actinidia arguta (A. arguta) has been widely used in Asian countries as a traditional medicinal herb to treat inflammation-related diseases, such as gastritis, bronchitis, and arthritis. AIM OF THE STUDY: The inhibitory effect of A. arguta leaves' extract (AA) on inflammasome activation was investigated to verify its traditional use in treating inflammation-related diseases. MATERIALS AND METHODS: Bone marrow-derived macrophages (BMDMs) primed by lipopolysaccharide (LPS) were activated by selective inflammasome stimulators, and the effect of AA on inflammasome activation was investigated. A monosodium urate crystal (MSU)-induced peritonitis mouse model was used to study the in vivo efficacy of AA on inflammasome activation. RESULTS: In the in vitro study, AA regulated NLRP3 ubiquitination and apoptosis-associated speck-like protein containing a CARD (ASC) oligomerization, leading to the inhibition of NLRP3 inflammasome-mediated interleukin (IL)-1ß secretion. The inhibitory effect of AA on inflammasome activation in vitro was further confirmed in vivo using an MSU-induced peritonitis mouse model. CONCLUSION: AA provided scientific evidence, substantiating the traditional claims for its use in the treatment of inflammation and inflammation-mediated metabolic disorders, including gout.
Subject(s)
Actinidia , Anti-Inflammatory Agents/pharmacology , Inflammasomes/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Plant Extracts/pharmacology , Animals , Anti-Inflammatory Agents/therapeutic use , Caspase 1/metabolism , Cells, Cultured , Female , Interleukin-1beta/metabolism , Lipopolysaccharides/pharmacology , Macrophages/drug effects , Macrophages/metabolism , Mice, Inbred C57BL , Peritonitis/chemically induced , Peritonitis/drug therapy , Peritonitis/metabolism , Plant Extracts/therapeutic use , Plant Leaves , Ubiquitination , Uric AcidABSTRACT
Antimicrobial peptides (AMPs), also called host defense peptides, particularly those with amphipathic helical structures, are emerging as target molecules for therapeutic development due to their immunomodulatory properties. Although the antimicrobial activity of AMPs is known to be exerted primarily by permeation of the bacterial membrane, the mechanism underlying its anti-inflammatory activity remains to be elucidated. We report potent anti-inflammatory activity of WALK11.3, an antimicrobial model peptide with an amphipathic helical conformation, in lipopolysaccharide (LPS)-stimulated RAW264.7 cells. This peptide inhibited the expression of inflammatory mediators, including nitric oxide, COX-2, IL-1ß, IL-6, INF-ß, and TNF-α. Although WALK11.3 did not exert a major effect on all downstream signaling in the MyD88-dependent pathway, toll-like receptor 4 (TLR4)- mediated pro-inflammatory signals were markedly attenuated in the TRIF-dependent pathway due to inhibition of the phosphorylation of STAT1 by attenuation of IRF3 phosphorylation. WALK11.3 specifically inhibited the endocytosis of TLR4, which is essential for triggering TRIF-mediated signaling in macrophage cells. Hence, we suggest that specific interference with TLR4 endocytosis could be one of the major modes of the anti-inflammatory action of AMPs. Our designed WALK11 peptides, which possess both antimicrobial and anti-inflammatory activities, may be promising molecules for the development of therapies for infectious inflammation.
Subject(s)
Anti-Infective Agents/pharmacology , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Macrophages/drug effects , Macrophages/metabolism , Peptides/pharmacology , Adaptor Proteins, Vesicular Transport/metabolism , Animals , Anti-Infective Agents/chemistry , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Cell Line/drug effects , Cyclooxygenase 2/metabolism , Drug Evaluation, Preclinical/methods , Inflammation Mediators/metabolism , Interleukin-1beta/metabolism , Interleukin-6/metabolism , Lipopolysaccharide Receptors/metabolism , Lipopolysaccharides/pharmacology , Mice , Nitric Oxide/metabolism , Peptides/chemistry , Signal Transduction/drug effects , Toll-Like Receptor 4/metabolismABSTRACT
ETHNOPHARMACOLOGICAL RELEVANCE: Impatiens textori Miq. (I. textori, Balsaminaceae) is a traditional medicinal herb used for centuries to treat several inflammatory related skin infections and allergic disorders in Asian countries. AIM OF THE STUDY: In this study, we elucidated the effects of whole plant extracts of I. textori on inflammasome activation using in vitro and in vivo models. MATERIALS AND METHODS: LPS-stimulated murine bone marrow macrophages were used to study the regulatory effect of I. textori extract (IT) on inflammasome activation. ATP, nigericin and MSU were used as danger-associated molecules to activate the NLRP3 inflammasome. An LPS-induced acute lung injury (ALI) mouse model was used to study the in vivo effect of IT on inflammasome activation. RESULTS: IT treated at 25, 50, and 100µg/mL concentrations suppressed interleukin-1ß secretion through the attenuation of NLRP3 inflammasome activation (p<0.001 at 100µg/mL) leading to the decreased amount of ASC oligomerization and caspase-1 maturation. For the in vivo model, IT inhibited the NLRP3 expression and cell recruitment at the lung tissue in the ALI mouse model. CONCLUSION: IT exhibited potent anti-inflammatory effects via the attenuation of NLRP3 inflammasome activation supporting the traditional claims and may provide a valuable therapeutic strategy in treating various inflammation-related disorders.
