Fig. 6

Schematic hypothesis about interleukin (IL)-13 synthesis induced through Smad and mitogen-activated protein kinase (MAPK) pathways in response to transforming growth factor (TGF)-β in T cells of patients with systemic sclerosis. TGF-β binds first to its type II receptor (TβRII), which then recruits and phosphorylates the type I receptor (TβRI), leading to activin receptor-like kinase (ALK5) activation within the receptor complex. The TβRI–TβRII complex then phosphorylates Smad 2/3 proteins, which complex with Smad4 to accumulate in the nucleus and act as transcription factors of target genes. In the non-Smad pathway, the TβRI–TβRII complex transmits its signal through other factors, such as by the Ras-extracellular signal-regulated kinase (Ras-ERK) pathway, TGF-β-activated kinase (TAK), c-Jun N-terminal kinase (JNK) and p38-MAPK pathways. Under activation, these factors translocate to the nucleus and regulate the expression of target genes. We observed that the upregulated IL-13 expression induced by TGF-β occurs via GATA-3 transcription factor modulation through Smad3 and p38-MAPK signaling pathways, which is reversed by the specific Smad3 inhibitor SIS3 or by the specific p38 inhibitor SB203580, respectively. Additionally, the ALK5-specific inhibition by SB431542 abolishes the TGF-β-induced Smad3 phosphorylation. CBP CREB-binding protein, COL1A collagen type I alpha, MCP-1 monocyte chemoattractant protein 1, SBE Smad-binding element, α-SMA α-smooth muscle actin