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Release of prostaglandin E(2) and nitric oxide from spinal microglia is dependent on activation of p38 mitogen-activated protein kinase.
Anesth Analg 2010; 111(2):554-60A&A

Abstract

BACKGROUND

The spinal release of prostaglandins (PGs), nitric oxide (NO), and cytokines has been implicated in spinal nociceptive processing. Microglia represent a possible cell of origin for these proexcitatory mediators. Spinal microglia possess Toll-like receptor 4 (TLR4) and neurokinin 1 (NK1) receptors, and both receptors play a significant role in peripheral nerve injury- and inflammation-induced spinal sensitization. Accordingly, we examined the properties of the cascades activated by the respective targets, which led to the release of PGE(2) and an increase in nitrite (NO(2)(-)) (a marker of NO) from cultured rat spinal microglia.

METHODS

Spinal microglia isolated from Sprague-Dawley neonatal rats were cultured with lipopolysaccharide (LPS) or substance P (SP) alone, with LPS in combination with SP, and with LPS in the presence of each inhibitor of cyclooxygenase (COX), NO synthase 2 (NOS2) or p38 mitogen-activated protein kinase (p38), or minocycline for 24 hours and 48 hours. Concentrations of PGE(2) and NO(2)(-) in culture supernatants were measured using an enzyme immunoassay and a colorimetric assay, respectively.

RESULTS

Application of LPS (a TLR4 ligand, 0.1 to 10 ng/mL) to cultured microglia produced a dose- and time-dependent increase in PGE(2) and NO(2)(-) production, whereas no effects were observed after incubation with SP (an NK1 agonist, up to 10(-5) M) alone or in combination with LPS. Antagonist studies with SC-560 (COX-1 inhibitor) and SC-236 (COX-2 inhibitor) showed that LPS-induced PGE(2) release was generated from both COX-1 and COX-2. LPS-induced NO release was suppressed by 1400W, an inhibitor of NOS2. Minocycline, an agent blocking microglial activation, and SB203580, an inhibitor of p38, both attenuated the LPS-induced PGE(2) and NO release. The 1400W, at the doses that suppressed NO release, also blocked increased PGE(2) release.

CONCLUSIONS

Our findings suggest that (a) activation of spinal microglia via TLR4 but not NK1 receptors produces PGE(2) and NO release from these cells; (b) the evoked PGE(2) release is generated by both COX-1 and COX-2, and (c) the COX-PGE(2) pathway is regulated by p38 and NOS2. Taken together with our previous in vivo work, the current findings emphasize that p38 in spinal microglia is a key player in regulating production of pronociceptive molecules, such as PGE(2) and NO.

Authors+Show Affiliations

Department of Laboratory Sciences, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi, Japan.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

20610553

Citation

Matsui, Tomohiro, et al. "Release of Prostaglandin E(2) and Nitric Oxide From Spinal Microglia Is Dependent On Activation of P38 Mitogen-activated Protein Kinase." Anesthesia and Analgesia, vol. 111, no. 2, 2010, pp. 554-60.
Matsui T, Svensson CI, Hirata Y, et al. Release of prostaglandin E(2) and nitric oxide from spinal microglia is dependent on activation of p38 mitogen-activated protein kinase. Anesth Analg. 2010;111(2):554-60.
Matsui, T., Svensson, C. I., Hirata, Y., Mizobata, K., Hua, X. Y., & Yaksh, T. L. (2010). Release of prostaglandin E(2) and nitric oxide from spinal microglia is dependent on activation of p38 mitogen-activated protein kinase. Anesthesia and Analgesia, 111(2), pp. 554-60. doi:10.1213/ANE.0b013e3181e3a2a2.
Matsui T, et al. Release of Prostaglandin E(2) and Nitric Oxide From Spinal Microglia Is Dependent On Activation of P38 Mitogen-activated Protein Kinase. Anesth Analg. 2010;111(2):554-60. PubMed PMID: 20610553.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Release of prostaglandin E(2) and nitric oxide from spinal microglia is dependent on activation of p38 mitogen-activated protein kinase. AU - Matsui,Tomohiro, AU - Svensson,Camilla I, AU - Hirata,Yuka, AU - Mizobata,Kanae, AU - Hua,Xiao-Ying, AU - Yaksh,Tony L, Y1 - 2010/07/07/ PY - 2010/7/9/entrez PY - 2010/7/9/pubmed PY - 2010/8/27/medline SP - 554 EP - 60 JF - Anesthesia and analgesia JO - Anesth. Analg. VL - 111 IS - 2 N2 - BACKGROUND: The spinal release of prostaglandins (PGs), nitric oxide (NO), and cytokines has been implicated in spinal nociceptive processing. Microglia represent a possible cell of origin for these proexcitatory mediators. Spinal microglia possess Toll-like receptor 4 (TLR4) and neurokinin 1 (NK1) receptors, and both receptors play a significant role in peripheral nerve injury- and inflammation-induced spinal sensitization. Accordingly, we examined the properties of the cascades activated by the respective targets, which led to the release of PGE(2) and an increase in nitrite (NO(2)(-)) (a marker of NO) from cultured rat spinal microglia. METHODS: Spinal microglia isolated from Sprague-Dawley neonatal rats were cultured with lipopolysaccharide (LPS) or substance P (SP) alone, with LPS in combination with SP, and with LPS in the presence of each inhibitor of cyclooxygenase (COX), NO synthase 2 (NOS2) or p38 mitogen-activated protein kinase (p38), or minocycline for 24 hours and 48 hours. Concentrations of PGE(2) and NO(2)(-) in culture supernatants were measured using an enzyme immunoassay and a colorimetric assay, respectively. RESULTS: Application of LPS (a TLR4 ligand, 0.1 to 10 ng/mL) to cultured microglia produced a dose- and time-dependent increase in PGE(2) and NO(2)(-) production, whereas no effects were observed after incubation with SP (an NK1 agonist, up to 10(-5) M) alone or in combination with LPS. Antagonist studies with SC-560 (COX-1 inhibitor) and SC-236 (COX-2 inhibitor) showed that LPS-induced PGE(2) release was generated from both COX-1 and COX-2. LPS-induced NO release was suppressed by 1400W, an inhibitor of NOS2. Minocycline, an agent blocking microglial activation, and SB203580, an inhibitor of p38, both attenuated the LPS-induced PGE(2) and NO release. The 1400W, at the doses that suppressed NO release, also blocked increased PGE(2) release. CONCLUSIONS: Our findings suggest that (a) activation of spinal microglia via TLR4 but not NK1 receptors produces PGE(2) and NO release from these cells; (b) the evoked PGE(2) release is generated by both COX-1 and COX-2, and (c) the COX-PGE(2) pathway is regulated by p38 and NOS2. Taken together with our previous in vivo work, the current findings emphasize that p38 in spinal microglia is a key player in regulating production of pronociceptive molecules, such as PGE(2) and NO. SN - 1526-7598 UR - https://www.unboundmedicine.com/medline/citation/20610553/Release_of_prostaglandin_E_2__and_nitric_oxide_from_spinal_microglia_is_dependent_on_activation_of_p38_mitogen_activated_protein_kinase_ L2 - http://dx.doi.org/10.1213/ANE.0b013e3181e3a2a2 DB - PRIME DP - Unbound Medicine ER -