1. Tumor necrosis factor alpha, citrullination, and peptidylarginine deiminase 4 in lung and joint inflammation
- Author
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Thomas F. Warner, Annette Gendron-Fitzpatrick, Ryan Rebernick, Miriam A. Shelef, Anthony P. Nicholas, Daeun Shim, Lennart K. A. Lundblad, Paul R. Thompson, and Mandar Bawadekar
- Subjects
0301 basic medicine ,Hydrolases ,Blotting, Western ,Arthritis ,Mice, Transgenic ,Inflammation ,Protein citrullination ,Arthritis, Rheumatoid ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Protein-Arginine Deiminase Type 4 ,Citrulline ,medicine ,Animals ,Humans ,Rheumatoid arthritis ,Lung ,030203 arthritis & rheumatology ,Peptidylarginine deiminase 4 ,Tumor Necrosis Factor-alpha ,business.industry ,Citrullination ,Pneumonia ,respiratory system ,medicine.disease ,Arthritis, Experimental ,respiratory tract diseases ,3. Good health ,030104 developmental biology ,medicine.anatomical_structure ,chemistry ,TNF-α ,Experimental arthritis ,Immunology ,Tumor necrosis factor alpha ,medicine.symptom ,business ,Protein Processing, Post-Translational ,Research Article - Abstract
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-α levels are high in rheumatoid arthritis; however, it is unknown if TNF-α can induce lung protein citrullination. The citrullinating enzyme peptidylarginine deiminase 4 (PAD4) exacerbates TNF-α-induced arthritis, but a role for PAD4 in lung citrullination and TNF-α-induced lung inflammation has not been explored. Our aim was to use TNF-α-overexpressing mice to clarify the intersection of TNF-α, citrullination, PAD4, arthritis, and lung inflammation. Methods Lung protein citrullination in wild-type mice, mice that overexpress TNF-α systemically (TNF+), TNF+PAD4+/+, and TNF+PAD4-/- mice was quantified by both gel electrophoresis using a citrulline probe and western blot. Hematoxylin and eosin (H&E)-stained lung sections from TNF+PAD4+/+ and TNF+PAD4-/- mice were scored for lung inflammation. H&E-stained ankle joint sections from mice that overexpress TNF-α 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-α only in the lungs do not develop arthritis. Conclusions PAD4 exacerbates lung inflammation downstream of TNF-α without having a major role in generalized protein citrullination in inflamed lungs. Also, TNF-α-induced lung inflammation is not sufficient to drive murine arthritis. Electronic supplementary material The online version of this article (doi:10.1186/s13075-016-1068-0) contains supplementary material, which is available to authorized users.
- Published
- 2016