Our results implicate a critical role for
Our results implicate a critical role for CXCR-1 in promoting the migration of colonic tumor cells. Expression of this receptor, but not CXCR-2, increased significantly because of the EMT (Fig. 3). Moreover, although Clone A Calcein acetoxymethyl ester express comparable levels of both IL-8 receptors, only CXCR-1 inhibition prevented the potent chemotactic effect of this cytokine in these cells (Fig. 5). As mentioned in Introduction, there is accumulating evidence to suggest that even when both receptors are present, distinct signaling pathways and cellular functions can be activated by the same ligand. Indeed, the different subcellular localization of these two receptors in Clone A cells (Fig. 4) supports this hypothesis. Consistent with our Clone A results, it is interesting to note that neutrophil chemotaxis also appears to be primarily mediated by CXCR-1, despite surface receptor expression of CXCR-1 and CXCR-2 and similar binding affinity for IL-8 , . Furthermore, in other colon carcinoma cell lines IL-8 has been reported as an autocrine growth factor regulating cellular proliferation . In this case, the growth affects of IL-8 appeared to be linked to cell density, and there was a differential expression of CXCR-1 and CXCR-2 as the cells approached confluency. In terms of regulation, both receptors undergo phosphorylation, desensitization, and internalization in response to IL-8 activation, at least in leukocytes , , . CXCR-2 internalizes more rapidly and is recycled more slowly to the cell surface than CXCR-1 . Although the mechanisms that underlie these differences in CXCR-1 and -2 are not well defined, it appears that the carboxy-terminus of each receptor plays a regulatory role , .
Finally, the data we have presented here provide an ideal complement to those findings recently reported by Heidemann et al. . In that study, the authors showed that stimulation of human intestinal microvascular endothelial cells (HIMEC) with IL-8 resulted in enhanced chemotaxis, proliferation rate, and phosphorylation of ERK 1/2. These changes are characteristic of angiogenesis, and in fact, the authors proposed that paracrine stimulation of the vascular endothelium by IL-8 produced, for example, by a colorectal adenocarcinoma, would promote angiogenesis. In this context, our results suggest that colon carcinoma cells that have undergone an EMT could provide the source of the chemokine for their model. Importantly, they observed that the IL-8 effects on the HIMEC cells were mediated by CXCR-2, not CXCR-1, in accordance with previously published observations . Our data extend this model, and highlight the possibility that tumor-derived IL-8 secretion may also promote migration of the tumor cells themselves, in an autocrine manner, via a different receptor. Clearly, the interface of these two events (increased angiogenesis and increased tumor cell migration) is likely to be of fundamental importance in promoting invasion.
Introduction It is now known that R5 virus predominantly uses the chemokine receptor-CCR5 (HIV-1 coreceptor) and is involved mainly in establishing a new infection and transmission. These viruses are macrophage-tropic. At the later stages of the disease, one usually finds virus that can use other coreceptors, particularly among them is the CXCR-4 (for recent review see Berger et al., 1999). The appearance of T-cell line-tropic syncytium-inducing (SI) isolates is often associated with the rapid decline of CD4+ cells and speedy progression of the disease. These chemokine receptors play an important role in HIV-1 transmission. Individuals who possess a homozygous deletion of 32 base-pair segment corresponding to the second extracellular loop of the 7-transmembrane G-coupled protein, are usually resistant to HIV-1 infection (Liu et al., 1986, Dean et al., 1996, Huang et al., 1996, Samson et al., 1996), and even heterozygous individuals (for the Δ32 allele of CCR5) show partial protection (Huang et al., 1996). This protection is not absolute (Biti et al., 1997, O’Brien et al., 1997, Theodorou et al., 1997), as CXCR-4 using viruses (X4) have been found in individuals who were homozygous for the Δ32 allele (Nelson et al., 1998). Therefore, it is essential that an antiviral approach based on coreceptors only, should also be directed against CXCR-4 coreceptors. Although a variety of chemokine receptors have been identified that act as HIV-1 coreceptors under in vitro conditions, only the above two coreceptors, namely CCR5 and CXCR-4, have been implicated to have an important physiological role in the viral spread (Zhang and Moore, 1999).