UMMS Affiliation

Department of Biochemistry and Molecular Pharmacology

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Document Type



Biochemistry | Enzymes and Coenzymes | Musculoskeletal Diseases | Rheumatology


BACKGROUND: The relationship between lung and joint inflammation in rheumatoid arthritis is poorly understood. Lung inflammation with resultant protein citrullination may trigger anti-citrullinated protein antibodies, inflammation, and arthritis. Alternatively, lung and joint inflammation may be two manifestations of a single underlying pathology. The lung has increased citrullination and TNF-alpha levels are high in rheumatoid arthritis; however, it is unknown if TNF-alpha can induce lung protein citrullination. The citrullinating enzyme peptidylarginine deiminase 4 (PAD4) exacerbates TNF-alpha-induced arthritis, but a role for PAD4 in lung citrullination and TNF-alpha-induced lung inflammation has not been explored. Our aim was to use TNF-alpha-overexpressing mice to clarify the intersection of TNF-alpha, citrullination, PAD4, arthritis, and lung inflammation.

METHODS: Lung protein citrullination in wild-type mice, mice that overexpress TNF-alpha systemically (TNF(+)), TNF(+)PAD4(+/+), and TNF(+)PAD4(-/-) mice was quantified by both gel electrophoresis using a citrulline probe and western blot. Hematoxylin and eosin (HandE)-stained lung sections from TNF(+)PAD4(+/+) and TNF(+)PAD4(-/-) mice were scored for lung inflammation. HandE-stained ankle joint sections from mice that overexpress TNF-alpha only in the lungs were assessed for arthritis.

RESULTS: TNF(+) mice have increased lung protein citrullination. TNF(+)PAD4(-/-) mice do not have significantly reduced lung protein citrullination, but do have decreased lung inflammation compared to TNF(+)PAD4(+/+) mice. Mice that overexpress TNF-alpha only in the lungs do not develop arthritis.

CONCLUSIONS: PAD4 exacerbates lung inflammation downstream of TNF-alpha without having a major role in generalized protein citrullination in inflamed lungs. Also, TNF-alpha-induced lung inflammation is not sufficient to drive murine arthritis.


Citrullination, Experimental arthritis, Lung, Peptidylarginine deiminase 4, Rheumatoid arthritis, TNF-α

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Copyright © The Author(s). 2016. Open Access.

DOI of Published Version



Arthritis Res Ther. 2016 Jul 22;18(1):173. doi: 10.1186/s13075-016-1068-0. Link to article on publisher's site

Journal/Book/Conference Title

Arthritis research and therapy

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Creative Commons Attribution 4.0 License
This work is licensed under a Creative Commons Attribution 4.0 License.