# Immunomodulatory Effects of Pentoxifylline: Profiling Data Based on RAW 264.7 Cellular Signaling
## 1 Introduction  
Pentoxifylline (PTX) is a methylxanthine derivative (1-(5-oxohexyl)-3,7-dimethylxanthine) that has been used for the past several decades to improve the blood rheological properties and treat symptoms associated with impaired microcirculation [1]. Other methylated xanthine compounds, which include caffeine, theophylline, aminophylline, and theobromine, are plant components and have similar major pharmacologic actions [2]. The major enzymatic action of cyclic nucleotide phosphodiesterase (PDEs) is the degradation of cyclic adenosine monophosphate (cAMP). PTX works as a nonselective inhibitor of PDEs, and therefore upregulates the effects of cAMP and adenosine-5\({}^{\prime}\)-triphosphate and increases erythrocyte distensibility. PTX reduces leukocyte adhesion to endothelial cells, enhances prostacyclin synthesis, and diminishes platelets aggregation. The accumulation of the above effects leads to capillary dilatation, a reduction in blood viscosity, and an improvement in peripheral microvasculature [3]. In recent studies, attention has been given to the possibility of treating PTX as an immunomododulatory agent. PTX has shown the ability to down-regulate pro-inflammatory cytokines, such as tumor necrosis factor-\(\alpha\) (TNF-\(\alpha\)) and interleukin 1 (IL-1). PTX inhibits TNF-\(\alpha\) synthesis by blocking transcriptional activity [4, 5]. A PTX-treated mice group showed significant TNF-\(\alpha\) reduction in a radiation-induced lung injury model [6]. [PERSON] et al. [7] performed a placebo-controlled randomized clinical trial in patients with non-alcoholic steatohepatitisitis. In comparison with the placebo-using group, PTX was reported tosignificantly reduce steatosis, lobular inflammation, and liver fibrosis. In a study of neonatal sepsis, PTX inhibited the production of inflammatory cytokines by microorganisms, particularly when used in combination with antimicrobial agents [8]. In a randomized controlled trial involving 120 newborns with late-onset sepsis and mean gestational age of 30 weeks, PTX administration decreased TNF-\(\alpha\) and C-reactive protein (CRP) levels, shortened the respiratory period and short-term hospitalization, and decreased incidence of disseminated intravascular coagulopathy [9]. However, there was no difference in mortality and short-term morbidity between PTX treated and untreated newborn sepsis [9; 10]. PTX has effects on inhibiting dermal fibroblast proliferation and extracellular matrix synthesis [11; 12] and increasing the activity of tissue collagenase [13]. Previous studies have shown the ability of PTX to reduce the fibrosis progress induced by external stress such as irradiation. PTX inhibits intracellular signaling in response to transforming growth factor-\(\beta\) (TGF-\(\beta\)), and connective tissue growth factor (CTGF). [PERSON] et al. [14] reported that PTX suppresses CTGF expression as well as the promoter effects of CTGF on kidney cells. However, in another study, no significant changes were found in TGF-\(\beta\) expression at either the mRNA or protein level in the irradiated rat heart model [15]. In postoperative peritoneal adhesion studies, PTX may reduce intraperitoneal adhesion formation by increasing peritoneal fibrinolysis activity and inhibiting angiogenesis and collagen synthesis [16]. Western blot analysis of radiation-induced pulmonary fibrosis models showed that PTX treatment suppressed the expression of plasminogen activator inhibitor-1 and fibronectin in irradiated lung tissues as well as in epithelial cells [17]. Osteoradinecrosis (ORN) is one of the significant side effects of radiotherapy; the pathogenesis of this disease remains unclear [18]. [PERSON] and [PERSON] [19] argued that ORN progression is related to the activation and deregulation of fibroblast activity, and atrophic tissue is formed at the irradiation site. It has been reported that PTX is effective in bone regeneration of ORN when used together withtocopherol [20]. [PERSON] et al.