The effect of CXCL1 on human fetal oligodendrocyte progenitor cells

Abstract

Chemokine CXCL1 is abundantly present in proliferative zones during brain development and in regions of remyelination, suggesting that it influences development of oligodendrocyte progenitors (OPC) in these regions. We studied in vitro the effects and possible mechanisms by which CXCL1 acts on human fetal OPC. In organotypic slice cultures of human fetal cortical ventricular/subventricular (VZ/SVZ) zones, blocking of CXCL1 signaling reduced significantly the proliferation of OPC. Moreover, exogenously added CXCL1 induced increase of OPC proliferation. Treatments of purified OPC cultures and cell depletion experiments demonstrated that this effect of CXCL1 was mainly indirect, mediated through astrocytes. We identified that CXCL1 acted through the extracellular signal regulated kinase (ERK1/2) pathway, activated primarily in astrocytes. In vitro, astrocytes stimulated with CXCL1 released several cytokines, but only the release of interleukin-6 (IL-6) was completely blocked by inhibition of ERK1/2 pathway. When released IL-6 was neutralized in slices, a decrease in OPC proliferation was demonstrated, while addition of IL-6 was able to return OPC proliferation in astrocyte-depleted slices to the control level. These results suggest that in the human fetal brain CXCL1 promotes proliferation of early OPC, acting in part through an ERK1/2-dependent pathway and release of IL-6 from astrocytes.

CXCR2 and CXCL4 regulate survival and self-renewal of hematopoietic stem/progenitor cells

“…Such a mechanism is supported by the clear evidence of complex heterodimeric interactions between chemokines, which lead to biological outcomes different from those of either of the individual component chemokines. [49][50][51] Similar to what happens in other systems, [52][53][54][55] our results showed that the CXCR2 signaling pathway played an important role in HSC maintenance. CXCR2 inhibition with the specific CXCR2 inhibitor SB225002 replicated the results for knockdown of CXCL4.…”

The chemokine CXCL1 induces proliferation in epithelial ovarian cancer cells by transactivation of the epidermal growth factor receptor

“…The involvement of MAPK signalling in CXCL1-induced proliferation of EOC was further demonstrated by the inhibition of proliferation of EOC by both PD98059 and the farnesyltransferase inhibitor FTI-277, which blocks Ras activity (Lerner et al 1995). Activation of ERK1/2 by CXCL1 has previously been reported in other cell types including astrocytes (Filipovic & Zecevic 2008), neutrophils (Fuhler et al 2005) and neurons (Xia & Hyman 2002). IL8 has also been shown to stimulate ERK1/2 phosphorylation in SKOV3 cells (Venkatakrishnan et al 2000).…”

The chemokine receptor CXCR2 is differentially regulated on glial cells in vivo but is not required for successful remyelination after cuprizone‐induced demyelination

“…Although also a very recent study (Filipovic and Zecevic, 2008) could show that CXCL1 promotes proliferation of early human OPC, the involvement of CXCR2 during maturation of OPC and therefore during remyelination remains still unclear.…”