RANTES and MIP-1α Activate Stats in T Cells

Abstract

RANTES1 (regulated on activation, normal T cell expressed and secreted) and MIP (macrophage inflammatory protein)-1␣ are potent chemoattractant cytokines (chemokines) for T cells (1-3). Accumulating evidence suggests that these CC or ␤-chemokines function as regulators of inflammatory and immunoregulatory processes (4 -15). Chemokines mediate their shared and different biologic effects through common receptors. Eight receptor cDNAs specific for the CC chemokines have been cloned to date, whose nine gene products share a seven transmembrane domain architecture linked to G-protein complexes (16 -19). A number of studies have examined chemokine-induced signal transduction, yet defined signaling pathways have not been elaborated. Interleukin-8, the main chemotactic cytokine for neutrophils, will stimulate serine/threonine protein kinases (20). Monocyte chemotactic protein (MCP)-1 will activate p42/44 mitogen-activated protein kinases (21). MCP-1-, MCP-2-, and MCP-3-induced monocyte chemotaxis can be blocked by both serine/threonine and tyrosine kinase inhibitors (22). MCP-1 and MCP-3 rapidly induce arachidonic acid in target monocytes (23). RANTES, MIP-1␣, and MCP-1, -2, and -3 have been shown to promote Ca 2ϩ mobilization in monocytes, eosinophils, basophils, and T cells (7, 21, 24 -27).Many cytokines and growth factors mediate their effects via activation of a common signal transduction pathway, the STAT pathway. Binding of the ligand to its specific transmembrane receptor results in receptor aggregation, which may involve single or multiple receptor chains. Receptor aggregation leads to the catalytic activation of receptor-associated cytoplasmic protein-tyrosine kinases, termed janus kinases (JAK) and phosphorylation-activation of latent monomeric signal transducers and activators of transcription, Stat proteins. Six Stat proteins have been identified to date. Receptor-associated phosphorylated Stats then dimerize via SH2-phosphotyrosyl interactions and translocate to the nucleus, where they bind to specific promoter sequences, thereby regulating gene expression (reviewed in Ref. 29). All Stat proteins, with the possible exception of Stat2, differentially bind to more than ten related DNA elements, which fit the consensus TTNNNNNAA (consensus STAT recognition element). Conserved structural motifs within the cytoplasmic domains among the cytokine receptors have been implicated as Jak and STAT recognition sites (30, 31). Although Jak-STAT signaling is likely a common feature of all cytokines, recent reports suggest that STAT activation is not necessarily exclusively mediated via Jak association with the cytoplasmic domains of receptors that constitute the cytokine receptor superfamily. Angiotensin II binding to its cognate seven transmembrane, G-protein-coupled receptor, activates Stat1, Stat2,.Apart from their potent chemotactic activities, there is accumulating evidence that CC chemokines are also capable of stimulating T cells in vitro (35)(36)(37). At M concentrations, RANTES-induced signaling in T cells is med...

Chemokines: attractive mediators of the immune response

“…In the context of chemokine-CCR5 interactions in T cells, these data infer that chemokine involvement in Stat activation will influence T cell activation mediated, in part, by cross-talk with the activated TCR. We have shown that CCL5 induces the expression of a putative Stat inducible gene, c-fos, in T cells [51]. The induction of c-fos gene expression correlated with the expression of CCR5.…”

“…It is now clear that ligand-induced chemokine receptor activation can also invoke Jak-Stat signaling, perhaps by a mechanism that requires receptor homodimerization and heterodimerization [39][40][41]47,49,50]. Nuclear extracts from Molt-4 and Jurkat T cells treated with CCL3 or CCL5 contained tyrosine phosphorylated Stat1:Stat1 and Stat1:Stat3 dimers that exhibited DNA-binding activity [51]. This activation was dependent on CCR5 gene expression.…”

Identification of the Cytoplasmic Domains of CXCR4 Involved in Jak2 and STAT3 Phosphorylation

“…Although SDF-1-mediated activation of other members of the Jak/STAT family has also been described (17)(18)(19), we focused our work on the Jak2/STAT3 pathway because of its major role in GPCR signal transduction (18,(35)(36)(37) and survival signals (57). GPCRs contain four cytoplasmic domains, three loops (ICL1-3) and a C terminus part, that are potentially able to recruit signaling molecules leading to activation of a wide variety of cellular responses after ligand binding.…”

“…Activation of the Jak2/STAT3 pathway was described in several chemokine receptors such as CCR2b, CXCR4, CCR5, and platelet-activating factor receptor (PAFR) (18,(35)(36)(37) and Jak2 is required for SDF-1␣-induced activation of PI 3-kinase, tyrosine phosphorylation of multiple focal adhesion proteins and chemotaxis of hematopoietic progenitor cells (19). Other GPCRs such as luteinizing hormone, angiotensin II, PAR-1, and serotonin 5-HT 2A receptors also activate Jak2 after ligand binding (38 -42) underlying the role of Jak2 in GPCR signaling.…”

Rheumatoid arthritis is a heterogeneous disease: Evidence for differences in the activation of the STAT‐1 pathway between rheumatoid tissues

“…A likely explanation would be that increased STAT-1 expression is a consequence of increased cytokine activity in the synovium. STAT-1 can be activated by a number of cytokines, including the type I and type II IFNs, interleukin-6 (IL-6), IL-9, IL-11, oncostatin M, and leukemia inhibitory factor, and by the chemokines RANTES and macrophage inflammatory protein 1␣ (43,44). Although the prototype STAT-1-inducing cytokine IFN␥ is barely detectable in the rheumatoid synovium, low doses of IFN␥ are able to sensitize the STAT-1 activation pathway, which has been shown to yield increased STAT-1 activity upon subsequent activation (40).…”