Hassett, S. and Moynagh, Paul N. and Reen, D. (2006) TNF-α is a mediator of the anti-inflammatory response in a human neonatal model of the non-septic shock syndrome. Pediatric Surgery International, 22 (1). pp. 24-30. ISSN 0179-0358

Preview

Download (347kB) | Preview

Abstract

The anti-inflammatory/immunoparalytic phase of the systemic inflammatory response syndrome (SIRS) following major insult (surgery, thermal/traumatic injury) is of major clinical importance in the neonate, during which the risk of infection is particularly great. Here, the mechanisms by which TNF-α production is suppressed in response to infection are largely unknown. We questioned whether TNF-α itself could be a critical mediator of this suppression. Monocytes, isolated from cord blood (n=3), were treated with LPS (100 ng/ml), TNF-α (10 ng/ml, +/− anti-TNF-α antibody) for 18 and 36 h. Cells were then restimulated with LPS (Gram −ve) or Pam-3-Cys (Gram +ve) for 24 h. This was also done in the presence of selective inhibitors of MAP kinases p38, MEK and JNK. TNF-α, IL-6, IL-10 and IL-8 were quantified by ELISA CD86 and HLA-DR expression were determined flow cytometrically. Cells stimulated with LPS for 24 h produced TNF-α (282 pg/ml), IL-10 (1,236 pg/ml), IL-6 (2,694 pg/ml) and IL-8 (2,144 pg/ml). In cells pre-exposed to TNF-α for 36 h, there was a significant suppression in TNF-α and IL-6 levels (9 and 221 pg/ml, respectively) (P<0.05) with minimal impact on IL-10 (1,206 pg/ml) and IL-8 levels (1,886 pg/ml). A similar effect was seen with Pam-3-Cys with a tenfold decrease in levels of TNF-α and IL-6 (86→8.5 pg/ml and 458→46 pg/ml, respectively) with no effect on IL-10 and IL-8 levels. Anti-TNF-α antibody negated this effect. Inhibition of p38 kinase reversed the TNF-α effect. Inhibition of the JNK and MEK kinases had no effect. A reduction in the expression of CD86 and HLA-DR was observed. This ex-vivo model of non-septic SIRS demonstrates that TNF-α, released during a major insult, can suppress subsequent monocyte responses to bacterial agents through p38 MAP kinase, making it a potential therapeutic target.

Item Type:	Article
Additional Information:	The definitive version of this article is available at Hassett, S., Moynagh, P. & Reen, D. Ped Surgery Int (2006) 22: 24. DOI:10.1007/s00383-005-1574-7
Keywords:	Neonatal sepsis; Monocyte tolerance; TNF-α;
Academic Unit:	Faculty of Science and Engineering > Biology
Item ID:	7203
Identification Number:	https://doi.org/10.1007/s00383-005-1574-7
Depositing User:	Professor Paul Moynagh
Date Deposited:	20 Jul 2016 10:01
Journal or Publication Title:	Pediatric Surgery International
Publisher:	Springer
Refereed:	Yes
URI:	http://link.springer.com
Use Licence:	This item is available under a Creative Commons Attribution Non Commercial Share Alike Licence (CC BY-NC-SA). Details of this licence are available here

Repository Staff Only(login required)

Item control page

Downloads

Origin of downloads