Cortisol synthesis in epidermis is induced by IL-1 and tissue injury.
Glucocorticoids (GCs) are known inhibitors of wound healing. In this study we report the novel finding that both keratinocytes in vitro and epidermis in vivo synthesize cortisol and how this synthesis regulates wound healing. We show that epidermis expresses enzymes essential for cortisol synthesis, including steroid 11 β-hydroxylase (CYP11B1), and an enzyme that controls negative feedback mechanism, 11β-hydroxysteroid dehydrogenase 2 (11βHSD2). We also found that cortisol synthesis in keratinocytes and skin can be stimulated by ACTH and inhibited by metyrapone (CYP11B1 enzyme inhibitor). Interestingly, IL-1β, the first epidermal signal of tissue injury, induces the expression of CYP11B1 and increases cortisol production by keratinocytes. Additionally, we found induction of CYP11B1 increased production of cortisol and activation of GR pathway during wound healing ex vivo and in vivo using human and porcine wound models, respectively. Conversely, inhibition of cortisol synthesis during wound healing increases IL-1β production, suggesting that cortisol synthesis in epidermis may serve as a local negative feedback to proinflammatory cytokines. Local GCs synthesis, therefore, may provide control of the initial proinflammatory response, preventing excessive inflammation upon tissue injury. Inhibition of GC synthesis accelerated wound closure in vivo, providing the evidence that modulation of cortisol synthesis in epidermis may be an important regulatory mechanism during wound healing.
Department of Medicine, Lenox Hill Hospital, New York, New York 10075, USA.
Sasa
S
Vukelic
Olivera
O
Stojadinovic
Irena
I
Pastar
Morgan
M
Rabach
Agata
A
Krzyzanowska
Elizabeth
E
Lebrun
Stephen C
SC
Davis
Sydney
S
Resnik
Harold
H
Brem
Marjana
M
Tomic-Canic
D000324:Adrenocorticotropic Hormone / Q000494:pharmacology; D000818:Animals; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004817:Epidermis / Q000293:injuries* / Q000378:metabolism* / Q000473:pathology; D006728:Hormones / Q000494:pharmacology; D006801:Humans; D006854:Hydrocortisone / Q000096:biosynthesis*; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D053583:Interleukin-1beta / Q000096:biosynthesis*; D015603:Keratinocytes / Q000378:metabolism* / Q000473:pathology; D008797:Metyrapone / Q000494:pharmacology; D013252:Steroid 11-beta-Hydroxylase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013552:Swine; D014945:Wound Healing / Q000187:drug effects / Q000502:physiology*
D004791:Enzyme Inhibitors; D006728:Hormones; D053583:Interleukin-1beta; D000324:Adrenocorticotropic Hormone; D013252:Steroid 11-beta-Hydroxylase; D006854:Hydrocortisone; D008797:Metyrapone
Ostomy Wound Manage. 2008 Oct;54(10):16-8, 20, 22-5
18927480
FASEB J. 2007 Jun;21(8):1844-56
17317724
J Exp Med. 2006 Sep 4;203(9):2057-62
16923850
Mol Cell Endocrinol. 1998 Mar 16;138(1-2):61-9
9685215
Ann N Y Acad Sci. 2004 Jun;1024:86-101
15265775
J Invest Dermatol. 1997 Feb;108(2):160-5
9008228
FASEB J. 2005 Aug;19(10):1332-4
15946990
Wound Repair Regen. 2007 Jan-Feb;15(1):71-9
17244322
Front Biosci. 2006 Sep 01;11:2230-48
16720310
Endocr Rev. 2000 Feb;21(1):55-89
10696570
J Invest Dermatol. 2001 May;116(5):633-40
11348449
FASEB J. 2001 Aug;15(10):1678-93
11481215
J Dermatol Sci. 1998 Jul;17(3):167-81
9697045
J Am Acad Dermatol. 1994 Apr;30(4):535-46
7512582
Mol Cell Endocrinol. 1982 Jul;27(2):157-68
6288491
J Invest Dermatol. 2010 Apr;130(4):1167-77
19727116
FEBS Lett. 1995 Oct 23;374(1):113-6
7589495
Mol Cell Endocrinol. 1994 Nov;105(2):R11-7
7859916
J Invest Dermatol. 2003 Jun;120(6):905-14
12787114
J Biol Chem. 2007 Feb 9;282(6):4021-34
17095510
J Invest Dermatol. 2006 Aug;126(8):1697-704
16845409
J Investig Dermatol Symp Proc. 1999 Sep;4(2):177-83
10536996
J Exp Med. 1994 Jun 1;179(6):1835-46
8195711
Horm Res. 2000;54(5-6):230-42
11595811
J Clin Endocrinol Metab. 2003 Jun;88(6):2384-92
12788832
Proc Natl Acad Sci U S A. 2007 Aug 7;104(32):13098-103
17670946
J Clin Invest. 2004 Feb;113(3):390-400
14755336
J Clin Endocrinol Metab. 2007 Mar;92(3):857-64
17200165
J Invest Dermatol. 2006 May;126(5):1177-8
16484985
Dev Dyn. 1997 Apr;208(4):447-53
9097017
Wound Repair Regen. 1996 Oct;4(4):411-20
17309691
N Engl J Med. 2005 Oct 20;353(16):1711-23
16236742
Wound Repair Regen. 1997 Jan-Mar;5(1):12-7
16984452
J Clin Endocrinol Metab. 2000 Nov;85(11):4060-8
11095433
Mol Cell Endocrinol. 2007 Feb;265-266:143-9
17197073
J Clin Invest. 2007 May;117(5):1219-22
17476353
J Psychosom Res. 2002 Oct;53(4):865-71
12377295
Am J Physiol Endocrinol Metab. 2005 Apr;288(4):E701-6
15572653
Horm Metab Res. 2007 Feb;39(2):71-84
17326003
J Invest Dermatol. 2005 May;124(5):1034-43
15854046
Science. 1988 Aug 5;241(4866):708-12
3041594
J Mol Med (Berl). 2007 Jun;85(6):589-601
17221218
Wound Repair Regen. 2008 Sep-Oct;16(5):585-601
19128254
Mol Cell Biol. 2002 Aug;22(15):5492-505
12101242
Horm Metab Res. 2007 Feb;39(2):85-95
17326004
Arthritis Res Ther. 2006;8(4):R108
16846535
Nat Immunol. 2005 Jan;6(1):73-9
15592472
Curr Opin Allergy Clin Immunol. 2001 Oct;1(5):469-76
11964729
J Invest Dermatol. 1990 Jun;94(6 Suppl):146S-150S
2141048
Am J Pathol. 2005 Jul;167(1):59-69
15972952
Microsc Res Tech. 1998 Sep 1;42(5):345-50
9766429
Endocrinology. 2004 Feb;145(2):941-50
14605004
J Invest Dermatol. 1998 Nov;111(5):850-7
9804349
Mol Cell Biol. 2000 Jun;20(12):4328-39
10825196
J Clin Endocrinol Metab. 2000 Jul;85(7):2519-25
10902803
J Mol Biol. 2005 Feb 4;345(5):1083-97
15644206
J Clin Endocrinol Metab. 2001 Nov;86(11):5121-6
11701663
Endocrinology. 2001 May;142(5):1982-9
11316764
J Biol Chem. 2002 Jul 19;277(29):26573-80
12000743
Eur J Endocrinol. 2002 Dec;147(6):795-802
12457455
FASEB J. 2006 Jan;20(1):76-86
16394270
J Steroid Biochem Mol Biol. 2001 Jul;78(1):77-81
11530287
Surg Technol Int. 2008;17:105-12
18802889
Mol Med. 2010 Mar;16(3-4):92-101
20069132
Biochim Biophys Acta. 2000 Mar 6;1474(1):1-4
10699483