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Identification of Cytokines That Might Enhance the Promoter Activity of HLA-B27

LIKE ZHAO, YOLY FONG, KAISA GRANFORS, JIERUO GU, and DAVID YU

ABSTRACT

Objective. Although the mechanism by which HLA-B27 induces ankylosing spondylitis is unclear, a minimum threshold of transcription is essential, a process controlled at the promoter. Our aim was to scan the effect of a panel of cytokines on the promoter of the HLA-B27 gene over serial timepoints.

Methods. The promoter region of B*2705 gene was cloned into a luciferase reporter, stably transfected into HeLa cells, and used to monitor the serial effect of 25 cytokines. Results of HLA-B27 promoter-reporter assays were compared to those of real-time polymerase chain reactions.

Results. After an initial delay, significant activation of the HLA-B27 promoter was observed with tumor necrosis factor-a (TNF-a), interferon-γ (IFN-γ), and IFN-ß. While early response of the HLA-B27 promoter was highest with TNF-a and IFN-γ, ultimately the highest activity was observed with IFN-ß.

Conclusion. The only promoter of HLA-B alleles studied in the past was that of HLA-B7, and always at only a single fixed timepoint of culture. This is the first study to show that activation of HLA-B27 promoter is a sequential event, and that TNF-a and IFN-ß are major participants at different timepoints. (First Release Mar 15 2008; J Rheumatol 2008;35:862-8)

Key Indexing Terms:

HLA-B27
PROMOTER
TUMOR NECROSIS FACTOR-a
INTERFERONS
ANKYLOSING SPONDYLITIS

From the Rheumatology Division, University of California Los Angeles, Los Angeles, California, USA; Department of Rheumatology, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China; and the Department of Bacterial and Inflammatory Diseases, National Public Health Institute, Turku, Finland.

Supported by the Nora Eccles Treadwell Foundation, The Academy of Finland, and the Sigrid Jusélius Foundation.

L. Zhao, MD, Postdoctoral Fellow, Rheumatology Division, University of California Los Angeles, Department of Rheumatology, Third Affiliated Hospital of Sun Yat-sen University; Y. Fong, Medical Student, Rheumatology Division, University of California Los Angeles; K. Granfors, PhD, Professor, Department of Bacterial and Inflammatory Diseases, National Public Health Institute; J. Gu, MD, Professor, Department of Rheumatology, Third Affiliated Hospital of Sun Yat-sen University; D. Yu, MD, Professor, Rheumatology Division, University of California Los Angeles.

Address reprint requests to Dr. D. Yu, 35-36 Rehabilitation Center, Rheumatology Division, University of California Los Angeles, 1000 Veteran Avenue, Los Angeles, CA 90024, USA. E-mail: dtyyu@ucla.edu

Accepted for publication October 19, 2007.