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J Steroid Biochem Mol Biol. 2019 Nov 26;198:105552. doi: 10.1016/j.jsbmb.2019.105552. [Epub ahead of print]

A mouse model for vitamin D-induced human cathelicidin antimicrobial peptide gene expression.

Author information

1
Department of Microbiology, Oregon State University, Corvallis, OR 97331, USA; Linus Pauling Institute, Oregon State University, Corvallis, OR 97331, USA.
2
Linus Pauling Institute, Oregon State University, Corvallis, OR 97331, USA; Department of Biochemistry and Biophysics, Oregon State University, Corvallis, OR 97331, USA.
3
Linus Pauling Institute, Oregon State University, Corvallis, OR 97331, USA; Nutrition Graduate Program, School of Biological & Population Health Sciences, College of Public Health & Human Sciences, Oregon State University, Corvallis, OR 97331, USA.
4
Department of Biochemistry and Biophysics, Oregon State University, Corvallis, OR 97331, USA; Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, Corvallis, OR 97331, USA.
5
Department of Biochemistry and Biophysics, Oregon State University, Corvallis, OR 97331, USA; Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, Corvallis, OR 97331, USA; Knight Cancer Institute, OHSU, Portland, OR 97239, USA; Department of Dermatology, Oregon Health & Science University (OHSU), Portland, OR 97239, USA.
6
Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, Corvallis, OR 97331, USA; Knight Cancer Institute, OHSU, Portland, OR 97239, USA.
7
Department of Surgery, Transplant & Holland Regenerative Medicine Program, University of Nebraska Medical Center, Omaha, NE 68198, USA.
8
Department of Dermatology, University of California San Diego, La Jolla, CA 92093, USA.
9
Division of Hematology/Oncology, Cedars-Sinai Medical Center, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90048, USA; Cancer Science Institute of Singapore, National University of Singapore, Singapore, 117599, Singapore.
10
Linus Pauling Institute, Oregon State University, Corvallis, OR 97331, USA; Department of Biochemistry and Biophysics, Oregon State University, Corvallis, OR 97331, USA. Electronic address: adrian.gombart@oregonstate.edu.

Abstract

In humans and other primates, 1,25(OH)2vitamin D3 regulates the expression of the cathelicidin antimicrobial peptide (CAMP) gene via toll-like receptor (TLR) signaling that activates the vitamin D pathway. Mice and other mammals lack the vitamin D response element (VDRE) in their CAMP promoters. To elucidate the biological importance of this pathway, we generated transgenic mice that carry a genomic DNA fragment encompassing the entire human CAMP gene and crossed them with Camp knockout (KO) mice. We observed expression of the human transgene in various tissues and innate immune cells. However, in mouse CAMP transgenic macrophages, TLR activation in the presence of 25(OH)D3 did not induce expression of either CAMP or CYP27B1 as would normally occur in human macrophages, reinforcing important species differences in the actions of vitamin D. Transgenic mice did show increased resistance to colonization by Salmonella typhimurium in the gut. Furthermore, the human CAMP gene restored wound healing in the skin of Camp KO mice. Topical application of 1,25(OH)2vitamin D3 to the skin of CAMP transgenic mice induced CAMP expression and increased killing of Staphylococcus aureus in a wound infection model. Our model can help elucidate the biological importance of the vitamin D-cathelicidin pathway in both pathogenic and non-pathogenic states.

KEYWORDS:

Cathelicidin; Cyp27b1; Innate immunity; Macrophage; TLR; Vitamin D

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