The role of interleukin-1 in wound biology. Part I: Murine in silico and in vitro experimental analysis.
BACKGROUND
Wound healing is a multistep, complex process that involves the coordinated action of multiple cell types. Conflicting results have been obtained when conventional methods have been used to study wound biology. Therefore, we analyzed the wound response in a mouse genetic model.


METHODS
We analyzed inflammatory mediators produced within incisional wounds induced in 16 inbred mouse strains. Computational haplotype-based genetic analysis of inter-strain differences in the level of production of 2 chemokines in wounds was performed. An in vitro experimental analysis system was developed to investigate whether interleukin (IL)-1 could affect chemokine production by 2 different types of cells that are present within wounds.


RESULTS
The level of 2 chemokines, keratinocyte-derived chemokine (KC) and macrophage inflammatory protein 1α, exhibited very large (75- and 463-fold, respectively) interstrain differences within wound tissue across this inbred strain panel. Genetic variation within Nalp1, an inflammasome component that regulates IL-1 production, correlated with the interstrain differences in KC and macrophage inhibitory protein 1α production. Consistent with the genetic correlation, IL-1β was shown to stimulate KC production by murine keratinocyte and fibroblast cell lines in vitro.


CONCLUSIONS
Genetic variation within Nalp1 could contribute to interstrain differences in wound chemokine production by altering the amount of IL-1 produced.
Hu
Yajing
Y
Department of Anesthesia, Stanford University, Stanford, USA.
Liang
Deyong
D
Li
Xiangqi
X
Liu
Hong-Hsing
HH
Zhang
Xun
X
Zheng
Ming
M
Dill
David
D
Shi
Xiaoyou
X
Qiao
Yanli
Y
Yeomans
David
D
Carvalho
Brendan
B
Angst
Martin S
MS
Clark
J David
JD
Peltz
Gary
G
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D054405:Chemokine CCL3 / Q000235:genetics / Q000378:metabolism*; D018925:Chemokines / Q000235:genetics / Q000378:metabolism*; D062109:Dermatologic Surgical Procedures; D023281:Genomics; D006239:Haplotypes; D007150:Immunohistochemistry; D018836:Inflammation Mediators / Q000378:metabolism*; D007375:Interleukin-1 / Q000235:genetics / Q000378:metabolism*; D053582:Interleukin-1alpha / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D015603:Keratinocytes / Q000276:immunology; D017737:Macrophages, Peritoneal / Q000276:immunology; D051379:Mice; D008815:Mice, Inbred Strains; D010641:Phenotype; D012867:Skin / Q000276:immunology; D013045:Species Specificity; D013997:Time Factors; D014945:Wound Healing / Q000235:genetics
D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; C496534:Ccl3 protein, mouse; D054405:Chemokine CCL3; D018925:Chemokines; D018836:Inflammation Mediators; D007375:Interleukin-1; D053582:Interleukin-1alpha; D053583:Interleukin-1beta; C529636:NALP1 protein, mouse; C074302:keratinocyte-derived chemokines