Universität zu Köln

Khan, Hina N., Perlee, Desiree, Schoenmaker, Lieke, Van Der Meer, Anne-Jan, Franitza, Marek, Toliat, Mohammad Reza, Nuernberg, Peter, Zwinderman, Aeilko H., van Der Poll, Tom and Scicluna, Brendon P. (2019). Leukocyte transcriptional signatures dependent on LPS dosage in human endotoxemia. J. Leukoc. Biol., 106 (5). S. 1153 - 1161. HOBOKEN: WILEY. ISSN 1938-3673

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Abstract

The host immune response is characterized by a complex interplay of signal-specific cellular transcriptional responses. The magnitude of the immune response is dependent on the strength of the external stimulus. Knowledge on leukocyte transcriptional responses altered in response to different stimulus dosages in man is lacking. Here, we sought to identify leukocyte transcriptional signatures dependent on LPS dose in humans. Healthy human volunteers were administered 1 ng/kg (n = 7), 2 ng/kg (n = 6), or 4 ng/kg (n = 7) LPS intravenously. Blood was collected before (pre-LPS) and 4 h after LPS administration. Total RNA was analyzed by microarrays and generalized linear models. Pathway analysis was performed by using Ingenuity pathway analysis. Leukocyte transcriptomes altered per LPS dosage were predominantly shared, with 47% common signatures relative to pre-LPS. A univariate linear model identified a set of 3736 genes that exhibited a dependency on differing LPS dosages. Neutrophil, monocyte, and lymphocyte counts explained 38.9% of the variance in the LPS dose-dependent gene set. A multivariate linear model including leukocyte composition delineated a set of 295 genes with a dependency on LPS dose. Evaluation of the 295 gene signature in patients with sepsis due to abdominal infections showed significant correlations. Promoter regions of the LPS dose gene set were enriched for YY1, EGR1, ELK1, GABPA, KLF4, and REL transcription factor binding sites. Intravenous injection of 1, 2, or 4 ng/kg LPS was accompanied by both shared and distinct leukocyte transcriptional alterations. These data may assist in assessing the severity of the insult in patients with abdominal sepsis.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Khan, Hina N. UNSPECIFIED UNSPECIFIED UNSPECIFIED Perlee, Desiree UNSPECIFIED UNSPECIFIED UNSPECIFIED Schoenmaker, Lieke UNSPECIFIED UNSPECIFIED UNSPECIFIED Van Der Meer, Anne-Jan UNSPECIFIED UNSPECIFIED UNSPECIFIED Franitza, Marek UNSPECIFIED UNSPECIFIED UNSPECIFIED Toliat, Mohammad Reza UNSPECIFIED UNSPECIFIED UNSPECIFIED Nuernberg, Peter UNSPECIFIED UNSPECIFIED UNSPECIFIED Zwinderman, Aeilko H. UNSPECIFIED UNSPECIFIED UNSPECIFIED van Der Poll, Tom UNSPECIFIED UNSPECIFIED UNSPECIFIED Scicluna, Brendon P. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-129804
DOI:	10.1002/JLB.4A0219-050R
Journal or Publication Title:	J. Leukoc. Biol.
Volume:	106
Number:	5
Page Range:	S. 1153 - 1161
Date:	2019
Publisher:	WILEY
Place of Publication:	HOBOKEN
ISSN:	1938-3673
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language INTENSIVE-CARE-UNIT; LIPOPOLYSACCHARIDE LPS; CYTOKINE RELEASE; DNA ELEMENTS; ENCYCLOPEDIA; INFLAMMATION; COAGULATION; EXPRESSION; SEPSIS Multiple languages Cell Biology; Hematology; Immunology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/12980