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Role of p38 MAPK in LPS induced pro-inflammatory cytokine and chemokine gene expression in equine leukocytes.
Vet Immunol Immunopathol. 2009 Jun 15; 129(3-4):192-9.VI

Abstract

Endotoxemia occurs when bacterial lipopolysaccharide (LPS) in the blood induces a dysregulated inflammatory response, resulting in circulatory shock and multi-organ failure. Laminitis is a common complication in endotoxemic horses and is frequently the reason for humane euthanasia of these cases. Blood leukocytes are a principal target of LPS in endotoxemia leading to activation of multiple signal transduction pathways involved in the induction of a number of pro-inflammatory genes. In other animal models, the p38 mitogen activated protein kinase (MAPK) pathway has been associated with induced expression of tumor necrosis factor-alpha (TNFalpha), interleukin (IL)-1beta, IL-6 and IL-8. The goal of this study was to determine the role of the p38 MAPK pathway in the induction of these pro-inflammatory cytokine and chemokine genes in LPS-stimulated equine leukocytes. Stimulation of equine peripheral blood leukocytes resulted in an increase in TNFalpha, IL-1beta, IL-6 and IL-8 mRNA levels. Pharmacological inhibition of p38 MAPK activity with SB203580 or SB202190 reduced the ability of LPS stimulation to increase mRNA concentrations for all four genes. However, only SB203580 pretreatment significantly reduced LPS-stimulated IL-1beta and IL-8 mRNA expression and only pretreatment with SB202190 significantly reduced LPS-stimulated TNFalpha and IL-6 mRNA expression. From this study we conclude TNFalpha, IL-1beta, IL-6 and IL-8 are induced upon LPS stimulation of equine leukocytes and that this induction of gene expression is dependent on the p38 MAPK pathway. However, there are differences in the efficacy of the p38 inhibitors tested here that may be explained by differences in specificity or potency. This study provides evidence for the use of selective p38 MAPK inhibitors as potential therapeutics for the treatment of equine endotoxemia.

Authors+Show Affiliations

Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC 27606, United States.No 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

19070370

Citation

Neuder, Laura E., et al. "Role of P38 MAPK in LPS Induced Pro-inflammatory Cytokine and Chemokine Gene Expression in Equine Leukocytes." Veterinary Immunology and Immunopathology, vol. 129, no. 3-4, 2009, pp. 192-9.
Neuder LE, Keener JM, Eckert RE, et al. Role of p38 MAPK in LPS induced pro-inflammatory cytokine and chemokine gene expression in equine leukocytes. Vet Immunol Immunopathol. 2009;129(3-4):192-9.
Neuder, L. E., Keener, J. M., Eckert, R. E., Trujillo, J. C., & Jones, S. L. (2009). Role of p38 MAPK in LPS induced pro-inflammatory cytokine and chemokine gene expression in equine leukocytes. Veterinary Immunology and Immunopathology, 129(3-4), 192-9. https://doi.org/10.1016/j.vetimm.2008.11.006
Neuder LE, et al. Role of P38 MAPK in LPS Induced Pro-inflammatory Cytokine and Chemokine Gene Expression in Equine Leukocytes. Vet Immunol Immunopathol. 2009 Jun 15;129(3-4):192-9. PubMed PMID: 19070370.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Role of p38 MAPK in LPS induced pro-inflammatory cytokine and chemokine gene expression in equine leukocytes. AU - Neuder,Laura E, AU - Keener,Jamie M, AU - Eckert,Rachael E, AU - Trujillo,Jennifer C, AU - Jones,Samuel L, Y1 - 2008/11/07/ PY - 2008/12/17/entrez PY - 2008/12/17/pubmed PY - 2009/8/19/medline SP - 192 EP - 9 JF - Veterinary immunology and immunopathology JO - Vet Immunol Immunopathol VL - 129 IS - 3-4 N2 - Endotoxemia occurs when bacterial lipopolysaccharide (LPS) in the blood induces a dysregulated inflammatory response, resulting in circulatory shock and multi-organ failure. Laminitis is a common complication in endotoxemic horses and is frequently the reason for humane euthanasia of these cases. Blood leukocytes are a principal target of LPS in endotoxemia leading to activation of multiple signal transduction pathways involved in the induction of a number of pro-inflammatory genes. In other animal models, the p38 mitogen activated protein kinase (MAPK) pathway has been associated with induced expression of tumor necrosis factor-alpha (TNFalpha), interleukin (IL)-1beta, IL-6 and IL-8. The goal of this study was to determine the role of the p38 MAPK pathway in the induction of these pro-inflammatory cytokine and chemokine genes in LPS-stimulated equine leukocytes. Stimulation of equine peripheral blood leukocytes resulted in an increase in TNFalpha, IL-1beta, IL-6 and IL-8 mRNA levels. Pharmacological inhibition of p38 MAPK activity with SB203580 or SB202190 reduced the ability of LPS stimulation to increase mRNA concentrations for all four genes. However, only SB203580 pretreatment significantly reduced LPS-stimulated IL-1beta and IL-8 mRNA expression and only pretreatment with SB202190 significantly reduced LPS-stimulated TNFalpha and IL-6 mRNA expression. From this study we conclude TNFalpha, IL-1beta, IL-6 and IL-8 are induced upon LPS stimulation of equine leukocytes and that this induction of gene expression is dependent on the p38 MAPK pathway. However, there are differences in the efficacy of the p38 inhibitors tested here that may be explained by differences in specificity or potency. This study provides evidence for the use of selective p38 MAPK inhibitors as potential therapeutics for the treatment of equine endotoxemia. SN - 0165-2427 UR - https://www.unboundmedicine.com/medline/citation/19070370/Role_of_p38_MAPK_in_LPS_induced_pro_inflammatory_cytokine_and_chemokine_gene_expression_in_equine_leukocytes_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0165-2427(08)00736-8 DB - PRIME DP - Unbound Medicine ER -