TLR agonists regulate PDGF-B production and cell proliferation through TGF-beta/type I IFN crosstalk.
Transforming growth factor-beta (TGF-beta) and type I interferon (IFN) autocrine/paracrine loops are recognized as key mediators of signaling cascades that control a variety of cellular functions. Here, we describe a novel mechanism by which Toll-like receptor (TLR) agonists utilize these two autocrine/paracrine loops to differentially regulate the induction of PDGF-B, a growth factor implicated in a number of diseases ranging from tumor metastasis to glomerulonephritis. We demonstrate that CpG-specific induction of PDGF-B requires activation of Smads through TGFbeta1 autocrine/paracrine signaling. In contrast, polyinosinic:polycytidylic acid strongly represses CpG's as well as its own intrinsic ability to induce PDGF-B mRNA through type I IFN-mediated induction of Smad7, a negative regulator of Smad3/4. Furthermore, we have shown that this crosstalk mechanism translates into similar regulation of mesangial cell proliferation. Thus, our results demonstrate the importance of crosstalk between TGF-beta and type I IFNs in determining the specificity of TLR-mediated gene induction.
Chow
Edward K
EK
Molecular Biology Institute, University of California Los Angeles, Los Angeles, CA 90095, USA.
O'connell
Ryan M
RM
Schilling
Stephen
S
Wang
Xiao-Fan
XF
Fu
Xin-Yuan
XY
Cheng
Genhong
G
D048868:Adaptor Proteins, Signal Transducing / Q000502:physiology; D000818:Animals; D000943:Antigens, Differentiation / Q000502:physiology; D002460:Cell Line; D049109:Cell Proliferation; D002478:Cells, Cultured; D018899:CpG Islands / Q000502:physiology; D007370:Interferon Type I / Q000502:physiology*; D053592:Interleukin-1 Receptor-Associated Kinases; D050527:Mesangial Cells / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B / Q000502:physiology; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000502:physiology; D011070:Poly I-C / Q000378:metabolism; D020574:Proto-Oncogene Proteins c-sis / Q000096:biosynthesis*; D012333:RNA, Messenger / Q000378:metabolism; D011971:Receptors, Immunologic / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D051901:Smad4 Protein / Q000378:metabolism; D051906:Smad7 Protein / Q000502:physiology; D051193:Toll-Like Receptors / Q000819:agonists*; D016212:Transforming Growth Factor beta / Q000378:metabolism / Q000502:physiology*; D053773:Transforming Growth Factor beta1; D015854:Up-Regulation
D048868:Adaptor Proteins, Signal Transducing; D000943:Antigens, Differentiation; D007370:Interferon Type I; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D020574:Proto-Oncogene Proteins c-sis; D012333:RNA, Messenger; D011971:Receptors, Immunologic; D051901:Smad4 Protein; C490810:Smad4 protein, mouse; D051906:Smad7 Protein; C497807:Smad7 protein, mouse; C508961:Tgfb1 protein, mouse; D051193:Toll-Like Receptors; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D017853:Phosphotransferases (Alcohol Group Acceptor); D053592:Interleukin-1 Receptor-Associated Kinases; C507774:Irak4 protein, mouse; D011070:Poly I-C