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<p>Snakebites are a worldwide public health problem with high-cost treatment in many countries. <i>Crotalus</i> genus snakes, commonly known as rattlesnakes, cause the most lethal snakebites in Brazil. <i>Crotalus</i> ssp envenomation is characterised by systemic neurotoxicity, myotoxicity, renal failure and minor local effects. Despite the knowledge of envenomation’s pathogenesis, the impact of <i>Crotalus</i> venom on adipose tissue (AT) cells is unknown. AT is an endocrine organ capable of releasing diverse immunomodulatory molecules, including prostaglandin E<sub>2</sub> (PGE<sub>2</sub>). Herein, we investigated the effects of <i>Crotalus durissus terrificus</i> venom (CdtV) on preadipocytes in vitro, focussing on the release of PGE<sub>2</sub> and mechanisms involved. CdtV (5 and 10&#xa0;μg/mL) induced a marked release of PGE<sub>2</sub> by preadipocytes (3–24&#xa0;h) compared to controls. Pre-treatment of cells with SC-560 or NS-398, selective inhibitors for cyclooxygenase (COX)-1 and COX-2 enzymes, respectively, decreased CdtV-induced PGE<sub>2</sub> release after 24&#xa0;h. CdtV (1 and 10&#xa0;μg/mL) did not change COX-1 protein expression by preadipocytes, but induced COX-2 protein expression at all time intervals evaluated. Pre-treating preadipocytes with AH6809, an inhibitor of the PGE<sub>2</sub> EP2 receptor, significantly increased the CdtV-induced PGE<sub>2</sub> release. EP1, EP3, or EP4 receptor antagonists did not change the CdtV-induced PGE<sub>2</sub> release. Additionally, CdtV did not alter the EP2 receptor protein expression in preadipocytes. These findings demonstrate that CdtV activates preadipocytes to produce PGE<sub>2</sub> via COX-1 activation and COX-2 protein expression and PGE<sub>2</sub> triggers a negative feedback loop via EP2 for its own production. These results highlight AT as another target for CdtV that may contribute to envenomation.</p>

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Crotalus durissus terrificus snake venom activates 3T3-L1 preadipocytes to release PGE2, which depends on COX-2 expression and is modulated by PGE2 EP2 receptor

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  • 发表日期：

    2025年6月23日

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  • Danilo Santos Teixeira,
  • Rodrigo Maia-Marques,
  • Catarina Teixeira

摘要

Snakebites are a worldwide public health problem with high-cost treatment in many countries. Crotalus genus snakes, commonly known as rattlesnakes, cause the most lethal snakebites in Brazil. Crotalus ssp envenomation is characterised by systemic neurotoxicity, myotoxicity, renal failure and minor local effects. Despite the knowledge of envenomation’s pathogenesis, the impact of Crotalus venom on adipose tissue (AT) cells is unknown. AT is an endocrine organ capable of releasing diverse immunomodulatory molecules, including prostaglandin E2 (PGE2). Herein, we investigated the effects of Crotalus durissus terrificus venom (CdtV) on preadipocytes in vitro, focussing on the release of PGE2 and mechanisms involved. CdtV (5 and 10 μg/mL) induced a marked release of PGE2 by preadipocytes (3–24 h) compared to controls. Pre-treatment of cells with SC-560 or NS-398, selective inhibitors for cyclooxygenase (COX)-1 and COX-2 enzymes, respectively, decreased CdtV-induced PGE2 release after 24 h. CdtV (1 and 10 μg/mL) did not change COX-1 protein expression by preadipocytes, but induced COX-2 protein expression at all time intervals evaluated. Pre-treating preadipocytes with AH6809, an inhibitor of the PGE2 EP2 receptor, significantly increased the CdtV-induced PGE2 release. EP1, EP3, or EP4 receptor antagonists did not change the CdtV-induced PGE2 release. Additionally, CdtV did not alter the EP2 receptor protein expression in preadipocytes. These findings demonstrate that CdtV activates preadipocytes to produce PGE2 via COX-1 activation and COX-2 protein expression and PGE2 triggers a negative feedback loop via EP2 for its own production. These results highlight AT as another target for CdtV that may contribute to envenomation.