Functional Inactivation of CXC Chemokine Receptor 4–mediated Responses through SOCS3 Up-regulation

Abstract

Hematopoietic cell growth, differentiation, and chemotactic responses require coordinated action between cytokines and chemokines. Cytokines promote receptor oligomerization, followed by Janus kinase (JAK) kinase activation, signal transducers and transactivators of transcription (STAT) nuclear translocation, and transcription of cytokine-responsive genes. These include genes that encode a family of negative regulators of cytokine signaling, the suppressors of cytokine signaling (SOCS) proteins. After binding their specific receptors, chemokines trigger receptor dimerization and activate the JAK/STAT pathway. We show that SOCS3 overexpression or up-regulation, stimulated by a cytokine such as growth hormone, impairs the response to CXCL12, measured by Ca2+ flux and chemotaxis in vitro and in vivo. This effect is mediated by SOCS3 binding to the CXC chemokine receptor 4 receptor, blocking JAK/STAT and Gαi pathways, without interfering with cell surface chemokine receptor expression. The data provide clear evidence for signaling cross-talk between cytokine and chemokine responses in building a functional immune system.

CXCR4-mediated Suppressor of Cytokine Signaling Up-regulation Inactivates Growth Hormone Function

“…induced STAT activation leads to SOCS3 up-regulation and interference with chemokine signaling and function (17). Here we show that GH-mediated JAK/STAT pathway activation is blocked in cells pretreated with chemokines.…”

“…RNA samples were resolved on denaturing formaldehyde-agarose gels and transferred to nylon membrane (Hybond Nϩ; Amersham Biosciences). Membranes were hybridized with 32 P-labeled cDNA from pEF-FLAG-I/mSOCS1, /mSOCS3, and ␤-actin (17). In some cases, mice received intravenous injections of CXCL12 (1 g in 200 l of sterile PBS) or PBS followed by an intravenous injection of GH (0.1 g in 100 l of sterile PBS); spleen and liver were extracted, and total RNA was processed as above.…”

“…SOCSs also have a regulatory role in other receptor systems, including the IGF-1 (16) and chemokine receptors (17), suggesting that SOCS proteins may have wide-ranging effects on signaling cascades (18).…”

Alternative implication of CXCR4 in JAK2/STAT3 activation in small cell lung cancer

“…The tight association of STAT3 activation with transformation and tumour progression makes it an attractive molecular target for novel cancer therapeutics development and many substances have been tested for their effect on STAT3 (Deng et al, 2007). Although a link was found between CXCR4 and STAT3 in different cells, such as haematopoietic progenitor cells (Zhang et al, 2001) or a fibrosarcoma cell line (Soriano et al, 2002), there are no reports on STAT3 signalling in SCLC so far. Because of previously reported links between CXCR4 and JAK/STAT signalling and potential of this pathway to provide drug targets, we were interested in whether this pathway is involved in SCLC.…”

KSHV-GPCR and CXCR2 transforming capacity and angiogenic responses are mediated through a JAK2-STAT3-dependent pathway

“…Knowing about the transforming capacity of KSHV-GPCR and CXCR2 and its similarities in signaling together with the transforming capacity of STAT3 signaling which is known to be induced by other cytokine receptors, for example, IL-6 (Heinrich et al, 1998) or chemokine receptors, for example, CXCR4 (Vila-Coro et al, 1999;Soriano et al, 2002), or CCR2B (Mellado et al, 1998) we were interested whether the JAK-STAT-3 pathway was induced by the KSHV-GPCR and CXCR2, and whether it plays a role in mediating the transforming abilities.…”