Molecular and Cellular Biochemistry

, Volume 462, Issue 1–2, pp 51–59 | Cite as

Up-regulation of interferon-stimulated gene 15 and its conjugation machinery, UbE1L and UbcH8 expression by tumor necrosis factor-α through p38 MAPK and JNK signaling pathways in human lung carcinoma

  • Wannee Lertsooksawat
  • Ariyaphong WongnoppavichEmail author
  • Kongthawat ChairatvitEmail author


Interferon-stimulated gene 15 (ISG15) is a member of the family of ubiquitin-like proteins. Similar to ubiquitin, conjugation of ISG15 to cellular proteins requires cascade reactions catalyzed by at least 2 enzymes, UbE1L and UbcH8. Expression of ISG15 and its conjugates is up-regulated in many cancer cells, yet the underlying mechanism of up-regulation is still unclear. In this study, we showed that TNF-α, similar to the response by IFN-β, could directly induce expression of ISG15 and its conjugation machinery, UbE1L and UbcH8, in human lung carcinoma, A549. The early response of their expression was effectively blocked by specific inhibitors of p38 MAPK (SB202190) and JNK (SP600125), but not by B18R, a soluble type-I IFN receptor. In addition, luciferase reporter assay together with serial deletions and site-directed mutagenesis identified a putative C/EBPβ binding element in the ISG15 promoter, which is necessary to the response by TNF-α. Taken together, expression of ISG15 and ISG15 conjugation machinery in cancer cells is directly up-regulated by TNF-α via p38 MAPK and JNK pathways through the activation of C/EBPβ binding element in the ISG15 promoter. This study provides a new insight toward understanding the molecular mechanism of ISG15 system and inflammatory response in cancer progression.


Cancer Inflammation ISG15 TNF-α 



This research project is supported by Mahidol University and Faculty of Dentistry, Mahidol University, and Ph.D. Research Grant, Faculty of Dentistry, Mahidol University (Grant No. 2560).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

11010_2019_3609_MOESM1_ESM.tif (92 kb)
Supplementary Fig. 1The chemical structures of SP600125, SB202190, U0126, wortmannin, and PDTC. (TIFF 91 kb)
11010_2019_3609_MOESM2_ESM.tif (124 kb)
Supplementary Fig. 2Segments of UbE1L (a) and UbcH8 (b) promoter sequences with the putative C/EBPβ binding elements (boxed), and the interferon stimulated response element (ISRE; underlined). (TIFF 123 kb)


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© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Oral Biology, Faculty of DentistryMahidol UniversityBangkokThailand
  2. 2.Department of Pharmacology, Faculty of DentistryMahidol UniversityBangkokThailand
  3. 3.Department of Biochemistry, Faculty of MedicineChiang Mai UniversityChiang MaiThailand

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