FGF2 has multiple functions and is involved in a lot of diseases. We found serum levels of FGF2 elevated in patients with TAK. This finding was in accordance with previous study. In our research, FGF2 level did not correlate to clinical parameters and peripheral blood mononuclear cells, but were positively correlated with several cytokines. As FGF2 promotes angiogenesis and fibrosis, which are important process of TAK, we suspect this finding indicates the cross talk between FGF2 and othercytokines drive the vasa vasorum angiogenesis or media fibrosis.
We found levels of FGF-2 were negatively related to age and age of TAK onset. This result was consistent with previous finding that FGF2 levels could distinguish TAK from GCA when considered together with age at diagnosis (3). As we know, patients with TAK are younger than those with GCA. Although there is no clear explanation for this result, we speculate that young TAK patients may have more pronounced angiogenesis.
G-CSF is a myeloid growth factor produced by monocytes, macrophages, fibroblasts, and endothelial cells (7). It has been reported that G-CSF induced endothelial cells to migrate and proliferate and stimulate angiogenesis (8–9). The co-delivery of FGF-2 and G-CSF was superior to either factor alone in promoting angiogenesis in a murine limb ischemic modeland mature vessel formation (10).
Chemokine (C-C motif) ligand 2 (CCL2), CCL3 were significantly correlated with FGF2 level in serum. Chemokines were measured in 85 TA patients, and 28 age- and gender-matched healthy controls. Significantly increased levels of CCL2, CCL3 were observed in TA patients when compared to healthy controls (11). CCL2 can be induced by interleukin (IL)-6, tumor necrosis factor (TNF)-α and growth factors (12). Lichtenstein MP et al. reported that FGF2 induced the upregulation of CCL2 in the research on inflammatory actions of FGF2 in astrocytes (13). M2 phenotype macrophage was dominated in the vascular lesions of TAK patients. M2 phenotype have a higher angiogenic potential. FGF signaling for M2a- and PlGF signaling for M2c-induced angiogenesis as possible working mechanisms, yet, further research should elucidate the exact mechanism for M2-induced angiogenesis (14). CCL2 is produced by macrophages, although endothelial cells, smooth muscle cells and fibroblasts are either the origin of this protein. CCL2 is also an important factor for recruiting macrophages. The expression of CCL2 was colocalized with CD68 in TAK aortic adventitia. CCL2 increased in the adventitia of TAK patients. Vascular medial CCL2 levels were increased as well as serum levels (15–16). FGF2 driven angiogenesis is partly chemokine dependent. In vitro, chick embryo chorioallantoic membrane and murine matrigel plug angiogenesis assays showed FGF2 stimulated endothelium cells to produce CCL2 may promote angiogenesis (17).
In a study on the mechanism involved in the stem cell factor induced production of FGF2 and CCL3 in tracheal smooth muscle cells, Oliveira LC et al found FGF2 production were mediated by CCL3 production through c-Kit (18).
A study about mast cells in wound healing found mast cells stimulate fibroblast proliferation via IL-4 and FGF2 to produce extracellular matrix. FGF2, IL-4, and IL-8 contribute to neoangiogenesis, fibrinogenesis, or reepithelialization during the repair process (19).
IL-17 is a pro-inflammatory cytokine involved in a lot of autoimmune diseases. FGF2 synergized with interleukin-17 (IL-17) to induce genes for repairing of damaged epithelium through Act1-mediated direct signaling cross-talk (20). It was reported that FGF2 cooperates with IL-17 to promote ERK activation and induce pathogenesis of autoimmune arthritis (21).
Furthermore, we found marked expression of FGF2 was shown in aortic lesions of patients with TAK compared with those of noninflammatory aorta controls. This result indicated FGF2 participated in the pathogenesis locally in the aorta.
The increased FGF2 level in peripheral blood in TAK patients. The correlation between FGF2 and several other cytokines which are involved in the process of neoangiogenesis. The limitation of this study is lack of research on how FGF2 is involved in TAK pathogenesis. Further studies including in vivo and in vitro on FGF2 function in TAK are needed.