Modulation of Interleukin-12 activity in the presence of heparin.

Autor: Jayanthi S; Department of Chemistry and Biochemistry, University of Arkansas, Fayetteville, AR, USA., Koppolu BP; Department of Biomedical Engineering, University of Arkansas, Fayetteville, AR, USA.; Joint Department of Biomedical Engineering, North Carolina State University and the University of North Carolina-Chapel Hill, Raleigh, NC, USA., Nguyen KG; Cell and Molecular Biology Program, University of Arkansas, Fayetteville, AR, USA.; Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC, USA., Smith SG; Department of Biomedical Engineering, University of Arkansas, Fayetteville, AR, USA.; Joint Department of Biomedical Engineering, North Carolina State University and the University of North Carolina-Chapel Hill, Raleigh, NC, USA., Felber BK; Human Retrovirus Pathogenesis Section, Vaccine Branch-National Cancer Institute, Frederick, MD, United States., Kumar TKS; Department of Chemistry and Biochemistry, University of Arkansas, Fayetteville, AR, USA. sthalla@uark.edu.; Cell and Molecular Biology Program, University of Arkansas, Fayetteville, AR, USA. sthalla@uark.edu., Zaharoff DA; Department of Biomedical Engineering, University of Arkansas, Fayetteville, AR, USA. david_zaharoff@ncsu.edu.; Joint Department of Biomedical Engineering, North Carolina State University and the University of North Carolina-Chapel Hill, Raleigh, NC, USA. david_zaharoff@ncsu.edu.; Cell and Molecular Biology Program, University of Arkansas, Fayetteville, AR, USA. david_zaharoff@ncsu.edu.; Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC, USA. david_zaharoff@ncsu.edu.
Jazyk: angličtina
Zdroj: Scientific reports [Sci Rep] 2017 Jul 13; Vol. 7 (1), pp. 5360. Date of Electronic Publication: 2017 Jul 13.
DOI: 10.1038/s41598-017-05382-1
Abstrakt: Glycosaminoglycans (GAGs), especially heparin and heparan sulfate (HS), modulate the functions of numerous cytokines. The aims of this multidisciplinary research were to characterize heparin binding to interleukin-12 (IL-12) and determine the mechanism(s) by which heparin influences IL-12 bioactivity. Heparin and HS were found to bind human IL-12 (hIL-12) with low micromolar affinity and increase hIL-12 bioactivity by more than 6-fold. Conversely, other GAGs did not demonstrate significant binding, nor did their addition affect hIL-12 bioactivity. Biophysical studies demonstrated that heparin induced only minor conformational changes while size-exclusion chromatography and small angle X-ray scattering studies indicated that heparin induced dimerization of hIL-12. Heparin modestly protected hIL-12 from proteolytic degradation, however, this was not a likely mechanism for increased cytokine activity in vitro. Flow cytometry studies revealed that heparin increased the amount of hIL-12 bound to cell surfaces. Heparin also facilitated hIL-12 binding and signaling in cells in which both hIL-12 receptor subunits were functionally deleted. Results of this study demonstrate a new role for heparin in modulating the biological activity of IL-12.
Databáze: MEDLINE