# Immunomodulatory Effects of Pentoxifylline: Profiling Data Based on RAW 264.7 Cellular Signaling
## 4 Discussion
\begin{table}
\begin{tabular}{c c c c} \hline \hline
**Signaling** & **Up-Regulated** & **Unchanged** & **Down-Regulated** \\ \hline Proliferation \(\downarrow\) & & PCNA & Ki-67, CDK4, PLK4, MPM2, \\  & & & cyclin D2, Rb-1, EZF-1, MDM2 \\ Apoptosis \(\downarrow\) & BAX, APAF-1 & BAK, caspase 9 & p53, PARP, FASL, FADD, \\ Antioxidant and cellular & & & caspase 8 \\ protection & AP-1, SP-1, AMPK-1 & & NOS-1, SOD-1, GST \\ Angiogenesis & HIF, angiogenin, VEGF-C & VEGF-A, vWF, ET-1, CD31 & CMG2 \\ Osteogenesis \(\uparrow\) & OPG, RANKL, osteepontin, & osteonectin, ALP & Cathenpsin K \\  & RUNX2, osterix & & \\ Inflammation \(\downarrow\) & CD4, IL-10, MMP-1, MMP-2, & TLR3, CD31, CD68, lysozyme, & IL-1, IL-6, CD3, CD20, CD28, \\  & MMP-3, MMP-9, & TNF-\(\alpha\) & M-CSF, cathepsin K, LTA4H, \\  & & & CXCR4, COX-2 \\ Growth factor & IGF-1, HER1, HER2 & TGF-\(\beta\)1 & FGF-1, FGF-2, ER\(\beta\) \\ \hline \hline \end{tabular} Abbreviations: PCNA: proliferating cell nuclear antigen, Ki-67, CDK4: cyclin dependent kinase 4, PLK4: polo-like kinase 4, MPM2: mitotic protein monoclonal 2, Rb-1: retinoblastoma-1, MDM2: mouse double minute 2 homolog, BAX: Bcl-2 associated X, APAF: apoptotic protease activating factor 1, BAK: Bcl-2 homologous antagonist killer, PARP: poly-ADP ribose polymerase, FASL: ISA ligand, FADD: FAS-associated via death domain, API: activation factor-1, SP-1: specific protein-1, AMPK-1: AMP-activated protein kinase, NOS1: nitric oxide synthase 1, SOD-1: superoxide dismutase-1, GST: glutathione G-transferase, HE: hypoxia inducible factor, VEGF-A: vascular endothelial growth factor-A, VEGF-C: vascular endothelial growth factor-C, vWF: von Willebrand factor, ET-1: endothelin-1, CD31: cluster of differentiation 31, CMG2: capillary morphogenic protein 2, OPG: osteoprotogerin, RANKL: receptor activator of nuclear factor kappa-B ligand, RUNX: RUNY-related transcription factor 2, ALP: alkaline phosphatase, CD4: cluster of differentiation, IL-10: interleukin-1, MMP-1: matrix metalloproteinase-1, MMP-2: matrix metalloproteinase-2, MMP-3: matrix metalloproteinase-3, MMP-9: matrix metalloproteinase-9, TLR3: Toll like receptor 3, CD68: cluster of differentiation 68, TNF-\(\alpha\): tumor necrosis factor-\(\alpha\), IL-1: interleukin-1, IL-6: interleukin-10, CD3: cluster of differentiation 3, CD30: cluster of differentiation 20, CD28: cluster of differentiation, MC28: clover of differentiation, MC28: clover of differentiation, MC27: macrophage-colony stimulating factor, LTA4H: leukotriene-A+hydrolase, CXCR4: C-X- chemokine receptor 4, COX-2 cyclooxygenase-2, IGF-1: insulin growth factor-1, HER1: human epidermal growth factor receptor 1, HER2: human epidermal growth factor receptor 2, TGF-\(\beta\)1: transforming growth factor-\(\beta\)1, ER\(\beta\): estrogen receptor \(\beta\), \(\uparrow\): upregulation, \(\downarrow\): downregulation.  
\end{table} 
Table 2: Representative cellular signaling affected by Pentoxiflline in RAW 264.7 cells. PTX reduced the expression of KRAS, NRAS, HRAS, and pAKT. The expression of ERK-1 was slightly up-regulated, while JNK-1, Rab, PKC levels were changed less than 5% in response to PTX. These results suggest that PTX slightly reduced RAS signaling compared to non-treated controls. PTX is known to inhibit TNF-\(\alpha\) and the synthesis of other pro-inflammatory cytokines [35]. Inhibition of NFsB may be associated with the reduction of pro-inflammatory cytokines [36]. In this study, PTX showed gradual decreases in NFkB signaling-related proteins, however, TNF-\(\alpha\) was not significantly affected by PTX treatment in this study. Inflammation-related protein, IL-1, IL-6, CD28, M-CSF, MCP-1, MMP-10, hepcidin, cathepsin K, LT44H, CXCR4, and COX-2 were significantly downregulated. This feature is expected to reduce the cytokine storm that can occur in COVID-19 patients.