Immunomodulatory Effects of Pentoxifylline: Profiling Data Based on RAW 264.7 Cellular Signaling

Abstract

Pentoxifylline (PTX) is a methylxanthine derivative that has been developed as an immunomodulatory agent and an improvement of microcirculation. Osteoradionecrosis (ORN) is a serious complication of radiation therapy due to hypovascularity. Coronavirus disease 2019 (COVID-19) has spread globally. Symptoms for this disease include self-limiting respiratory tract illness to severe pneumonia and acute respiratory distress. In this study, the effects of PTX on RAW 264.7 cells were investigated to reveal the possibility of PTX as a therapeutic agent for ORN and COVID-19. To reveal PTX effects at the cellular level, protein expression profiles were analyzed in the PTX-treated RAW 264.7 cells by using immunoprecipitation high-performance liquid chromatography (IP-HPLC). PTX-treated RAW 264.7 cells showed increases in immunity- and osteogenesis-related proteins and concurrent decreases in proliferation-, matrix inflammation-, and cellular apoptosis-related proteins expressions. The IP-HPLC results indicate that PTX plays immunomodulatory roles in RAW 264.7 cells by regulating anti-inflammation-, proliferation-, immunity-, apoptosis-, and osteogenesis-related proteins. These results suggest that PTX may be used as supplement medications for ORN as well as for COVID-19.

Parsimonious Effect of Pentoxifylline on Angiogenesis: A Novel Pentoxifylline-Biased Adenosine G Protein-Coupled Receptor Signaling Platform

“…Arsenyan et al [ 28 ] showed that PTX did not significantly suppress the MMP-mediated endothelial invasion in their study on the human umbilical vein endothelial cell tube formation model. This contrasts with the findings of Seo et al [ 43 ], which show that MMP-2 was upregulated in the 24 h post administration of pentoxifylline yet down-regulated after 48 h in a mouse-derived macrophage cell line. These findings suggest that metalloproteinase levels may be transiently affected by pentoxifylline.…”

“…All of the included studies were laboratory studies that examined the ability of pentoxifylline to generate an effect on angiogenesis in various models. Fifteen studies were in vivo only [ 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 ], three studies were in vitro only [ 41 , 42 , 43 ], and four studies had both in vivo and in vitro models [ 44 , 45 , 46 , 47 ]. The in vitro studies used human cells [ 42 , 44 , 45 , 46 , 47 ] and mouse cell lines [ 41 , 43 , 44 , 45 ].…”

“…Fifteen studies were in vivo only [ 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 ], three studies were in vitro only [ 41 , 42 , 43 ], and four studies had both in vivo and in vitro models [ 44 , 45 , 46 , 47 ]. The in vitro studies used human cells [ 42 , 44 , 45 , 46 , 47 ] and mouse cell lines [ 41 , 43 , 44 , 45 ]. The in vivo studies were mainly conducted using mouse [ 29 , 31 , 34 , 37 , 38 , 45 , 47 ] and rat [ 30 , 32 , 33 , 35 , 39 , 40 , 44 ] models, but zebrafish embryos [ 36 ], rabbit [ 26 , 27 ], and monkey [ 26 , 27 , 28 ] models were used as well.…”

“…One study examined the embryonic development of zebrafish when exposed to pentoxifylline [ 36 ]. Furthermore, two in vitro studies examined macrophage models exposed to pentoxifylline and its effects on angiogenesis factor release [ 43 , 44 ]. Lastly, one in vitro study assessed the effect of pentoxifylline in a novel mouse embryo proepicardium model of angiogenesis and a mouse endothelial cell line [ 41 ].…”

“…Overall, the included studies did not demonstrate uniformity regarding the effects of pentoxifylline on angiogenesis. Of the 22 included studies, pentoxifylline was found to have antiangiogenic effects in 16 studies [ 26 , 27 , 28 , 29 , 30 , 31 , 32 , 34 , 36 , 37 , 38 , 41 , 44 , 45 , 46 , 47 ], proangiogenic effects in 4 studies [ 35 , 39 , 40 , 43 ], and no effect at all on angiogenesis in 2 studies [ 33 , 42 ].…”