The research interests in my laboratory are (1) molecular and cellular regulation in helper T (T_H) cell differentiation; (2) regulation of IL-4/10/21 cytokine gene expressions by post-translational modified c-Maf; (3) role of transcription factor c-Maf in iNKT cell differentiation; (4) regulation of CD4 T cell nucleotide metabolism by c-Maf in cancer immunity; (5) regulation of IL-2 cytokine gene by transcription factor Ets-1; (6) regulation of IL-23/IL-17-axis by galectin-3; (7) role of novel chemokine Fam19a4 in inflammation, (8) role of CBP phosphorylation and microbiota in mucosal immunity, and (9) role of Ak4 in the metabolism and inflammation of inflammatory macrophages.

Chin WY, He CY, Chow TW, Yu QY, Lai LC, Miaw SC*. Adenylate kinase 4 Promotes Inflammatory Gene Expression via Hif1a and AMPK in Macrophages. FRONTIERS IN IMMUNOLOGY. 2021 MAR 15; 12: 630318. doi: 10.3389/fimmu.2021.630318 (*Corresponding author).

Macrophages comprise the front line of defense against various pathogens. Classically activated macrophages (M1), induced by IFN-g and LPS, highly express inflammatory cytokines and contribute to inflammatory processes. By contrast, alternatively activated macrophages (M2) are induced by IL-4 and IL-13, produce IL-10, and display anti-inflammatory activity. Adenylate kinase 4 (Ak4), an enzyme that transfers phosphate group among ATP/GTP, AMP, and ADP, is a key modulator of ATP and maintains the homeostasis of cellular nucleotides which is essential for cell functions. However, its role in regulating the function of macrophages is not fully understood. Here we report that Ak4 expression is induced in M1 but not M2 macrophages. Suppressing the expression of Ak4 in M1 macrophages with shRNA or siRNA enhances ATP production and decreases ROS production, bactericidal ability and glycolysis in M1 cells. Moreover, Ak4 regulates the expression of inflammation genes, including Il1b, Il6, Tnfa, Nos2, Nox2, and Hif1a, in M1 macrophages. We further demonstrate that Ak4 inhibits the activation of AMPK and forms a positive feedback loop with Hif1a to promote the expression of inflammation-related genes in M1 cells. Furthermore, RNA-seq analysis demonstrates that Ak4 also regulates other biological processes in addition to the expression of inflammation-related genes in M1 cells. Interestingly, Ak4 does not regulate M1/M2 polarization. Taken together, our study uncovers a potential mechanism linking energy consumption and inflammation in macrophages.

Li TC, Liu CC, Lee YZ, Hsu YH, Chiang CF, Miaw SC*, Lin WL*. Combination Therapy of Pulsed-Wave Ultrasound Hyperthermia and Immunostimulant OK-432 Enhances Systemic Antitumor Immunity for Cancer Treatment. INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY. 2020 APR 13; 108(1):140-149. (*Co-corresponding author)

Micro-metastases are mainly responsible for tumor recurrence after treatment. One potential way to overcome the challenge of undetectable small micro-metastases is to induce systemic antitumor immunity. In this study, we used pulsed-wave ultrasound hyperthermia and local injection of immunostimulant OK-432 to enhance the antitumor immune response. These hypotheses were tested in bilateral and rechallenged tumor models. The results showed that the growth of the distal untreated tumors was also affected by the enhanced antitumor immunity.

博士後研究：劉芷君

博士班:：秦偉堯

碩士班：(碩二)  、(碩一) 左華嵩、吳靖彤

大學部： 陳弘之

1. Chin WY, He CY, Chow TW, Yu QY, Lai LC, Miaw SC*. Adenylate kinase 4 Promotes Inflammatory Gene Expression via Hif1a and AMPK in Macrophages. FRONTIERS IN IMMUNOLOGY. 2021 MAR 15; 12: 630318. doi: 10.3389/fimmu.2021.630318 (*Corresponding author).
2. Li TC, Liu CC, Lee YZ, Hsu YH, Chiang CF, Miaw SC*, Lin WL. Combination Therapy of Pulsed-Wave Ultrasound Hyperthermia and Immunostimulant OK-432 Enhances Systemic Antitumor Immunity for Cancer Treatment. INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY. 2020 APR 13; 108(1):140-149. (*Co-corresponding author)
3. Yu JS, Hamada M, Ohtsuka S, Yoh K, Takahashi S, Miaw SC*. Differentiation of IL-17-Producing Invariant Natural Killer T Cells Requires Expression of the Transcription Factor c-Maf. FRONTIERS IN IMMUNOLOGY. 2017 OCT 27; 8:1399. doi: 10.3389/fimmu.2017.01399. (*Corresponding author)
4. 4.    Ho IC, Miaw SC. Regulation of IL-4 Expression in Immunity and Diseases. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY. 2016; 941:31-77.
5. Liu CC, Lai CY, Yen WF, Lin YH, Chang HH, Tai TS, Lu YJ, Tsao HW, Ho IC, Miaw SC*. Reciprocal regulation of c-Maf tyrosine phosphorylation by Tec and Ptpn22. PLOS ONE. 2015 MAY; 10(5):e0127617. (*Corresponding author)
6. Tsao HW, Tai TS, Tseng W, Chang HH, Grenningloh R, Miaw SC*, Ho IC. Ets-1 facilitates nuclear entry of NFAT proteins and their recruitment to the IL-2 promoter. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA. 2013 SEP; 110(39):15776-15781. (*Co-corresponding author)
7. Wu SY, Yu JS, Liu FT, Miaw SC*, Wu-Hsieh BA. Galectin-3 negatively regulates dendritic cell production of IL-23/IL-17-axis cytokines in infection by Histoplasma capsulatum. THE JOURNAL OF IMMUNOLOGY. 2013 APR; 190(7):3427-3437. (*Co-corresponding author)
8. Lai CY, Lin SY, Wu CK, Yeh LT, Sytwu HK, Miaw SC*. Tyrosine phosphorylation of c-Maf enhances the expression of IL-4 gene. THE JOURNAL OF IMMUNOLOGY. 2012 AUG; 189(4):1545-1550.   (*Corresponding author)
9. Miaw SC#, Chen JS, Hsieh PC, Liu CY, Chung MH, Chen PC, Chang ML, Chen FL, Kung JT, Wang LF. CD44-deficient mice do not exhibit impairment of epidermal Langerhans cell migration to lymph nodes after epicutaneous sensitization with protein. JOURNAL OF INVESTIGATIVE DERMATOLOGY. 2010 JUN; 130: 2674-2677. (#First author)
10. Lin BS, Tsai PY, Hsieh WY, Tsao HW, Liu MW, Grenningloh R, Wang LF, Ho IC, Miaw SC*. SUMOylation attenuates c-Maf-dependent IL-4 expression. EUROPEAN JOURNAL OF IMMUNOLOGY. 2010 APR; 40: 1174-1184. (*Corresponding author. This is a cover article)