4-1BB and the Epigenetic Regulations of This Molecule

Abstract

4-1BB, a master regulator of our defense system, is present on several kinds of immune cells and has different functions in immune responses based on specific conditions. An expression of this molecule on T lymphocytes, antigen-presenting cells (APCs) and pathogenic cells directs immune responses by a costimulatory signal of 4-1BB and its ligand, 4-1BBL. Under abnormal conditions, such as inflammation and hypoxia, 4-1BB and 4-1BBL are also induced on nonimmune cells including epithelial cells, endothelial cells, smooth muscle cells, and cardiac myocytes. Recently, 4-1BB has been found on brite adipocytes; it is identified as a specific marker for this type of fat cells. An increase in acetylated histone by histone deacetylase inhibitors (HDACi) leads to an elevation of 4-1BB and 4-1BBL expression and major histocompatibilitycomplex expression on T-cell lymphoma and other tumor cell lines, which enhance the activities of APCs and cytotoxic T lymphocytes to improve antitumor immune responses. Conversely, 4-1BB signaling triggered by a soluble 4-1BB receptor or anti-4-1BB antibodies strengthens the anticancer effect of HDACi by regulating both effector and regulatory T cells. Therefore, further investigations into the epigenetic regulations of 4-1BB/4-1BBL interaction will give us more meaningful information to develop new methods to prevent disorders in human beings such as cancer, obesity, autoimmune and infectious diseases.

Childhood Obesity Is a High-risk Factor for Hypertriglyceridemia: A Case-control Study in Vietnam

“…These factors regulate the induction and development of obesity via controlling the balance in the activity between white and thermogenic adipocytes; these cells function to store or dissipate energy in mammals [ 27 – 29 ]. At the molecular level, genetics, nutrition, and developmental stage regulate the genes for white fat expansion such as mesoderm specific transcript (MEST) and Sfrp5 secreted frizzled-related sequence protein 5 (Sfrp5), as well as the genes for the induction and function of thermogenic adipocytes (e.g., uncoupling protein 1, peroxisome proliferator-activated receptor gamma coactivator 1-alpha, and tumor necrosis factor receptor superfamily member 9 [CD137 or 4-1BB]) [ 19 , 20 , 22 , 30 ].…”

Human thermogenic adipocytes: a reflection on types of adipocyte, developmental origin, and potential application

“…The increase in activation of adipose p53 in obese animals was recently found due to an elevated level of DNA damage in fat deport of mice fed a HF (Vergoni et al 2016). Notably, beta-adrenergic receptor agonists such isoproterenol and forskolin, which can induce browning of white fat and activate thermogenic function of brown/brite adipocytes to burn lipid (Chu-Dinh and Chu 2014;Chu and Tao 2017;Dinh-Toi Chu et al 2017b), can prevent obesity-induced p53 activation in rat (Zand et al 2016).…”

Brown and brite adipocytes: Same function, but different origin and response

“…Inducible brown adipocytes or brite adipocytes (beige adipocytes, brown-like fat cells) were first described in rodents [21][22][23]. Initially these adipocytes were found in traditional white fat depots of rodents which were exposed to cold or injected by β adrenergic receptor agonists [21][22][23][24]. Then, they were classified as a third type of adipocytes, brite adipocytes, beside classical brown and white fat cells.…”

“…Then, they were classified as a third type of adipocytes, brite adipocytes, beside classical brown and white fat cells. Brite adipocytes share the thermogenic function with brown adipocytes but they have a distinct developmental origin [5,6,24,25]. Notably, there is the evidence of fully functional brite adipocytes in both infant and adult humans [14,[25][26][27].…”