ArticleInnovation (Cambridge (Mass.))2021
Nicotine and its metabolite cotinine target MD2 and inhibit TLR4 signaling.
Article in Innovation (Cambridge (Mass.)), 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 29 citations in OpenAlex.
- The neuroimmune-glutamate hypothesis of addiction.Neuroscience and biobehavioral reviews · 2026Review
- Utility of the Recombinase Driver CX3CR1-ERT2 Rat Strain in Nicotine Self-Administration.Cells · 2026Article
- Major bioactive metabolites derived fromFrontiers in pharmacology · 2026Review
- Correlation between inflammatory markers and disease severity in ulcerative colitis.World journal of gastrointestinal surgery · 2025Article
- Article
- Target discovery-directed pharmacological mechanism elucidation of bioactive natural products.Medical review (2021) · 2025Review
- Quantitative analysis of drug-drug interactions among active components of Xuebijing in inhibiting LPS-induced TLR4 signaling and NO production.Scientific reports · 2025Article
- The association between active and passive tobacco smoke exposures and epilepsy in United States participants of the National Health and Nutrition Examination Survey (2013-2018).Frontiers in neurology · 2025Article
- Structural modifications to pregnane neurosteroids alter inhibition of LPS/Lipid A binding at the MD-2 activation site within the TLR4 signaling complex.Frontiers in immunology · 2025Article
- Nicotine is an Immunosuppressant: Implications for Women's Health and Disease.Journal of neuroimmunology · 2024Review
- Sphinganine recruits TLR4 adaptors in macrophages and promotes inflammation in murine models of sepsis and melanoma.Nature communications · 2024Article
- Dithymoquinone Analogues as Potential Candidate(s) for Neurological Manifestation Associated with COVID-19: A Therapeutic Strategy for Neuro-COVID.Life (Basel, Switzerland) · 2022Article
- ACT001 Inhibits TLR4 Signaling by Targeting Co-Receptor MD2 and Attenuates Neuropathic Pain.Frontiers in immunology · 2022Article
- Toll-Like Receptor 4: A Novel Target to Tackle Drug Addiction?Handbook of experimental pharmacology · 2022Article
- Molecular Basis of Artemisinin Derivatives Inhibition of Myeloid Differentiation Protein 2 by Combined in Silico and Experimental Study.Molecules (Basel, Switzerland) · 2021Article
- Cotinine: Pharmacologically Active Metabolite of Nicotine and Neural Mechanisms for Its Actions.Frontiers in behavioral neuroscience · 2021Review
Corrections and comments
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Authors and funding
12 authors at 5 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Nicotine is the principal alkaloid of tobacco often manufactured into cigarettes and belongs to a highly addictive class of drugs. Nicotine attenuates the neuroinflammation induced by microglial activation. However, the molecular target(s) underlying anti-inflammatory action of nicotine has not been fully understood. Considering the psychoactive substances morphine, cocaine, and methamphetamine act as xenobiotic-associated molecular patterns and can be specifically sensed by the innate immune receptor Toll-like receptor 4 (TLR4), here we sought to delineate whether nicotine and/or its metabolite cotinine may be recognized by the innate immune system via myeloid differentiation protein 2 (MD2), an accessory protein of TLR4 that is responsible for ligand recognition. MD2-intrinsic fluorescence titrations, surface plasmon resonance, and competitive displacement binding assays with curcumin (MD2 probe) demonstrated that both nicotine and cotinine targeted the lipopolysaccharide (LPS; TLR4 agonist) binding pocket of MD2 with similar affinities. The cellular thermal shift assay indicated that nicotine binding increased, while cotinine binding decreased, MD2 stability. These biophysical binding results were further supported by
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