IL1β Induces Mesenchymal Stem Cells Migration and Leucocyte Chemotaxis Through NF-κB

Abstract

Mesenchymal stem cells are often transplanted into inflammatory environments where they are able to survive and modulate host immune responses through a poorly understood mechanism. In this paper we analyzed the responses of MSC to IL-1β: a representative inflammatory mediator. Microarray analysis of MSC treated with IL-1β revealed that this cytokine activateds a set of genes related to biological processes such as cell survival, cell migration, cell adhesion, chemokine production, induction of angiogenesis and modulation of the immune response. Further more detailed analysis by real-time PCR and functional assays revealed that IL-1β mainly increaseds the production of chemokines such as CCL5, CCL20, CXCL1, CXCL3, CXCL5, CXCL6, CXCL10, CXCL11 and CX3CL1, interleukins IL-6, IL-8, IL23A, IL32, Toll-like receptors TLR2, TLR4, CLDN1, metalloproteins MMP1 and MMP3, growth factors CSF2 and TNF-α, together with adhesion molecules ICAM1 and ICAM4. Functional analysis of MSC proliferation, migration and adhesion to extracellular matrix components revealed that IL-1β did not affect proliferation but also served to induce the secretion of trophic factors and adhesion to ECM components such as collagen and laminin. IL-1β treatment enhanced the ability of MSC to recruit monocytes and granulocytes in vitro. Blockade of NF-κβ transcription factor activation with IκB kinase beta (IKKβ) shRNA impaired MSC migration, adhesion and leucocyte recruitment, induced by IL-1β demonstrating that NF-κB pathway is an important downstream regulator of these responses. These findings are relevant to understanding the biological responses of MSC to inflammatory environments.Electronic supplementary materialThe online version of this article (doi:10.1007/s12015-012-9364-9) contains supplementary material, which is available to authorized users.

FGF2 induces RANKL gene expression as well as IL1β regulated MHC class II in human bone marrow-derived mesenchymal progenitor stromal cells

“…One publication using WB analysis, shows that IL1β does not activate ERK1/2 in hBM-MSC. 40 To our knowledge, no data exist with respect to the MAPKs induced by IFNγ in hBM-MSC. Therefore, we investigated by WB analysis whether the ERK1/2, p38 and JNK MAPKs were activated by FGF2, IL1β and IFNγ in hBM-MSC.…”

Inflammatory Microenvironment Changes the Secretory Profile of Mesenchymal Stem Cells to Recruit Mesenchymal Stem Cells

“…Supporting this notion is the fact (as showed in Fig. 5) that IL-1β can stimulate MSCs to secrete MIP-1α, RANTES, MIP-3α, ENA-78, GCP-2, IL-8 as well as GRO [18,41] and, TNF-α mainly accounts for hypersecretion of MIP-1α, RANTES, ENA-78, GCP-2, IL-8, GRO, and MCP-1 [15,43]. However, to the best of our knowledge, the influence of IL-6 on the secretome profile of MSCs has not been reported.…”

“…Besides, each of them has been identified as a powerful MSCs chemoattractant [18,19,20]. Herein, we utilized IL-1β, IL-6, and TNF-α to mimic the in vivo inflammatory microenvironment, as well as serve as a positive control for migration assay.…”

“…During in vitro expansion, MSCs constitutively secrete GRO chemokines [35,41,42], which in turn regulate the biological behaviors of MSCs through binding to their cell-surface cognate receptor, CXCR2 [22,36,37]. Besides, GRO production from MSCs can be significantly increased by the stimulation of IL-1β and TNF-α [15,18,41]. Taken together, it is reasonable to conclude that hypersecretion of GRO is a previously unrecognized molecular feature that specifically accompanies transplanted hBMSCs in inflammatory microenvironment and at least in part, GRO accounted for the enhanced capacity of transplanted hBMSCs in recruiting endogenous hBMSCs.…”

“…They play important roles in inflammatory diseases by inducing various inflammatory cytokines and chemokines [16,17]. Moreover, IL-1β, IL-6 and TNF-α induce migration of MSCs by binding to the respective receptors and activating the corresponding downstream signals [18,19,20,21]. Thus, IL-1β, IL-6 and TNF-α may regulate the secretome of MSCs and are ideally suited for imitating the in vivo inflammatory microenvironment.…”