Desensitization of CXC Chemokine Receptor 4, Mediated by IL-16/CD4, Is Independent of p56lckEnzymatic Activity

Abstract

CCR5 and CXC chemokine receptor 4 (CXCR4) are coreceptors for CD4 as defined by HIV-1 glycoprotein (gp) 120 binding. Pretreatment of T cells with gp120 results in modulation of both CCR5 and CXCR4 responsiveness, which is dependent upon p56lck enzymatic activity. The recent findings that pretreatment of T cells with a natural CD4 ligand, IL-16, could alter cellular responsiveness to macrophage-inflammatory protein-1β (MIP-1β) stimulation, prompted us to investigate whether IL-16 could also alter CXCR4 signaling. These studies demonstrate that IL-16/CD4 signaling in T lymphocytes also results in loss of stromal derived factor-1α (SDF-1α)/CXCR4-induced chemotaxis; however, unlike MIP-1β/CCR5, the effects were not reciprocal. There was no effect on eotaxin/CCR3-induced chemotaxis. Desensitization of CXCR4 by IL-16 required at least 10–15 min pretreatment; no modulation of CXCR4 expression was observed, nor was SDF-1α binding altered. Using murine T cell hybridomas transfected to express native or mutated forms of CD4, it was determined that IL-16/CD4 induces a p56lck-dependent inhibitory signal for CXCR4, which is independent of its tyrosine catalytic activity. By contrast, IL-16/CD4 desensitization of MIP-1β/CCR5 responses requires p56lck enzymatic activity. IL-16/CD4 inhibition of SDF-1α/CXCR4 signals requires the presence of the Src homology 3 domain of p56lck and most likely involves activation of phosphatidylinositol-3 kinase. These studies indicate the mechanism of CXCR4 receptor desensitization induced by a natural ligand for CD4, IL-16, is distinct from the inhibitory effects induced by either gp120 or IL-16 on CCR5.

IL-16 Promotes Leukotriene C4 and IL-4 Release from Human Eosinophils via CD4- and Autocrine CCR3-Chemokine-Mediated Signaling

“…Potentially, CD4 on eosinophils might be interacting with the PTX-sensitive CXCR4, which is expressed on eosinophils (47). Alternatively, PTX-sensitive receptors for PAF or for chemokines acting via CCR3 might be involved.…”

Synovial Fibroblasts from Patients with Rheumatoid Arthritis, Like Fibroblasts from Graves’ Disease, Express High Levels of IL-16 When Treated with Igs against Insulin-Like Growth Factor-1 Receptor

“…It renders pre-exposed T cells refractory to antigenic stimulation, promoting, as a consequence, anergy and enhanced Fas expression (32). IL-16 causes cross-desensitization of CCR5 and CXCR4 (33,34). Because RANTES uses the former, among other receptors, it is very likely that an important interplay exists between the two cytokines in the setting of inflammation.…”

Rapid Temporal Dynamics of Transcription, Protein Synthesis, and Secretion during Macrophage Activation

“…Reduction of Il16, a ligand of CD4 (77), in response to LPS stimulation could prevent cell cycle arrest, known to be induced after translocation of its N-terminal part to the nucleus (78). Alternatively, the previously described desensitization of chemokine receptors in target cells (79) like CCR5 could be omitted. CCR5 binds the cytokines Ccl4, Ccl5, and Ccl7 that were strongly induced in the presented dataset.…”