Regulation of Th1/Th2 polarization by tissue inhibitor of metalloproteinase-3 via modulating dendritic cells

Abstract

Tissue inhibitor of metalloproteinase-3 (TIMP-3) is one of a family of proteins inhibiting matrix metalloproteinases, which has also been identified as a mediator for checking inflammation. Meanwhile, it is well known that inflammation causes the activation of the immune response. However, it is not clear whether TIMP-3 plays a role in the immune system. In the present study, we demonstrated a novel function of TIMP-3 in Th1/Th2 polarization through its influence on the antigen-presenting cells. First, TIMP-3 was found strikingly up-regulated by IL-4 during the differentiation of human dendritic cells via the p38MAPK pathway. Second, the expression of costimulatory molecule-CD86 was repressed by TIMP-3. Besides, the induction of IL-12 in matured dendritic cells was significantly inhibited in a PI3K-dependent manner. IntroductionDendritic cells (DCs) are thought to be indispensable to initiate primary immune responses and play a pivotal role in linking the innate immunity and the adaptive immunity. 1,2 Their functions directly determine the outcome of T helper (Th) cell-mediated immune responses. 3,4 Normally, DCs reside in almost every tissue where they keep an immature state (imDCs) and serve as sentinels for the "dangerous" antigens. On stimulation with antigens or other signals, they undergo maturation and the matured DCs (mDCs) then migrate to the draining lymph nodes, where they present antigens to naive T cells. 5,6 In addition to their antigen presenting capability executed by the MHC class II molecules and the costimulatory molecules (CD40, CD80, and CD86), DCs also manipulate the nature and extent of the T cell-mediated immune responses through producing a variety of cytokines in response to the TLR ligands. 7 IL-12, which is deemed as a critical signal in T-cell polarization, together with IFN-␥, instructs naive T cell to shift toward a Th1 response, whereas IL-4 and a low level of IL-12 cause a Th2 response. In addition, the generation of regulatory T (Treg) cells requires 5,8,9 Therefore, the tissue environmental factors profoundly influence the adaptive immune responses through their modulation on DCs.Tissue inhibitors of metalloproteinases (TIMPs), specific inhibitors of matrix metalloproteinases (MMPs), consist of a family of 4 proteins that have been characterized so far. Independent of their inhibitory ability on MMPs, they also perform other biologic activities, such as promotion of cell proliferation, proapoptotic and antiapoptotic, and synaptic plasticity activities. 10,11 TIMP-3, a unique member of this family, is mainly sequestered to tissue extracellular matrix and is the only TIMP capable of inhibiting membrane bound MMPs, transmembrane MMPs, and sheddases, such as TNF-␣ converting enzyme. 12,13 TIMP-3 has been shown to act as a tumor suppressor in different cancer types, and loss of TIMP3 is closely associated with acquisition of tumorigenesis. 14-17 TIMP-3 can inhibit invasion and induce cell apoptosis in some specific cancer cell strains. [18][19][20][21][22] These observations indica...

Interleukin-4 and granulocyte-macrophage colony-stimulating factor mediates the upregulation of soluble vascular endothelial growth factor receptor-1 in RAW264.7 cells—a process in which p38 mitogen-activated protein kinase signaling has an important role

“…33,34 In this study, we observed increased levels of phosphorylated p38MAPK (p-p38) in RAW264.7 cells stimulated by IL-4 and GM-CSF. The p38MAPK inhibitor SB203580 abolished the upregulation of VEGFR1 mRNA and sVEGFR1 levels induced by IL-4 in RAW264.7 cells.…”

Decreased expression of IL-33 in immune thrombocytopenia

“…Plasma levels of cytokines reflect an imbalance of Th1/Th2 cells in ITP. In patients with active ITP, there is generally a Th1 polarization represented by aberrant Th1 cytokine expression [21,22]. An increased Th1/Th2 ratio that is detected by measuring mRNA expression of cytokines from PBMCs in the peripheral blood has been proposed to correlate with ITP disease activity [21,23,24].…”

Response gene to complement 32 (RGC-32) expression on M2-polarized and tumor-associated macrophages is M-CSF-dependent and enhanced by tumor-derived IL-4

“…Quantitative RT-PCR was performed in duplicate on a LightCycler 2.0 Instrument (Roche Diagnostic, Mannheim, Germany) and analyzed using the comparative 2 2DCt method as previously described. 25 GAPDH was used as an internal control. The primers for RGC-32, TNF-a, IL-1b, IL-6, TGF-b1 and GAPDH are listed in Supplementary Table 1.…”