The role of interleukin-1 in wound biology. Part II: In vivo and human translational studies.
BACKGROUND
In the accompanying paper, we demonstrate that genetic variation within Nalp1 could contribute to interstrain differences in wound chemokine production through altering the amount of interleukin (IL)-1 produced. We further investigate the role of IL-1 in incisional wound biology and its effect on wound chemokine production in vivo and whether this mechanism could be active in human subjects.


METHODS
A well-characterized murine model of incisional wounding was used to assess the in vivo role of IL-1 in wound biology. The amount of 7 different cytokines/chemokines produced within an experimentally induced skin incision on a mouse paw and the nociceptive response was analyzed in mice treated with an IL-1 inhibitor. We also investigated whether human IL-1β or IL-1α stimulated the production of chemokines by primary human keratinocytes in vitro, and whether there was a correlation between IL-1β and chemokine levels in 2 experimental human wound paradigms.


RESULTS
Administration of an IL-1 receptor antagonist to mice decreased the nociceptive response to an incisional wound, and reduced the production of multiple inflammatory mediators, including keratinocyte-derived chemokine (KC) and macrophage inhibitory protein (MIP)-1α, within the wounds. IL-1α and IL-1β stimulated IL-8 and GRO-α (human homologues of murine keratinocyte-derived chemokine) production by primary human keratinocytes in vitro. IL-1β levels were highly correlated with IL-8 in human surgical wounds, and at cutaneous sites of human ultraviolet B-induced sunburn injury.


CONCLUSIONS
IL-1 plays a major role in regulating inflammatory mediator production in wounds through a novel mechanism; by stimulating the production of multiple cytokines and chemokines, it impacts clinically important aspects of wound biology. These data suggest that administration of an IL-1 receptor antagonist within the perioperative period could decrease postsurgical wound pain.
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
D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D002478:Cells, Cultured; D002585:Cesarean Section; D054405:Chemokine CCL3 / Q000378:metabolism; D054360:Chemokine CXCL1 / Q000378:metabolism; D018925:Chemokines / Q000378:metabolism*; D062109:Dermatologic Surgical Procedures; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism*; D053590:Interleukin 1 Receptor Antagonist Protein / Q000494:pharmacology; D007375:Interleukin-1 / Q000378:metabolism*; D053582:Interleukin-1alpha / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D015603:Keratinocytes / Q000187:drug effects / Q000276:immunology* / Q000528:radiation effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010149:Postoperative Pain / Q000276:immunology / Q000517:prevention & control; D011247:Pregnancy; D016032:Randomized Controlled Trials as Topic; D012867:Skin / Q000187:drug effects / Q000276:immunology / Q000528:radiation effects; D013471:Sunburn / Q000276:immunology; D013997:Time Factors; D057170:Translational Research, Biomedical; D014945:Wound Healing / Q000187:drug effects
D000700:Analgesics; D000893:Anti-Inflammatory Agents; C475829:CXCL1 protein, human; C496534:Ccl3 protein, mouse; D054405:Chemokine CCL3; D054360:Chemokine CXCL1; D018925:Chemokines; D018836:Inflammation Mediators; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D053582:Interleukin-1alpha; D053583:Interleukin-1beta; D016209:Interleukin-8; C074302:keratinocyte-derived chemokines