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Δ 9 T etrahydrocannabinol attenuates Staphylococcal enterotoxin B ‐induced inflammatory lung injury and prevents mortality in mice by modulation of mi R ‐17‐92 cluster and induction of T ‐regulatory cells
Author(s) -
Rao R,
Nagarkatti P S,
Nagarkatti M
Publication year - 2015
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.13026
Subject(s) - proinflammatory cytokine , pharmacology , inflammation , syk , cytokine , immunology , chemistry , tensin , pten , pi3k/akt/mtor pathway , medicine , apoptosis , cancer research , signal transduction , tyrosine kinase , biochemistry
Background and Purpose Staphylococcal enterotoxin B (SEB) is a potent activator of Vβ8+T‐cells resulting in the clonal expansion of ∼30% of the T‐cell pool. Consequently, this leads to the release of inflammatory cytokines, toxic shock, and eventually death. In the current study, we investigated if Δ 9 tetrahydrocannabinol (THC), a cannabinoid known for its anti‐inflammatory properties, could prevent SEB‐induced mortality and alleviate symptoms of toxic shock. Experimental Approach We investigated the efficacy of THC against the dual administration (intranasal and i.p.) of SEB into C3H/HeJ mice based on the measurement of SEB‐mediated clinical parameters, including cytokine production, cellular infiltration, vascular leak, and airway resistance. In addition, the molecular mechanism of action was elucidated in vitro by the activation of splenocytes with SEB. Key Results Exposure to SEB resulted in acute mortality, while THC treatment led to 100% survival of mice. SEB induced the miRNA‐17‐92 cluster, specifically miRNA‐18a, which targeted Pten (phosphatase and tensin homologue), an inhibitor of the PI3K/Akt signalling pathway, thereby suppressing T‐regulatory cells. In contrast, THC treatment inhibited the individual miRNAs in the cluster, reversing the effects of SEB. Conclusions and Implications We report, for the first time a role for the mi RNA 17–92 cluster in SEB ‐mediated inflammation. Furthermore, our results suggest that THC is a potent anti‐inflammatory compound that may serve as a novel therapeutic to suppress SEB ‐induced pulmonary inflammation by modulating critical mi RNA involved in SEB ‐induced toxicity and death.