Fractalkine (CX3CL1) as an amplification circuit of polarized Th1 responses

Abstract

Fractalkine (FKN, CX3CL1) is a membrane-bound CX3C chemokine induced by primary proinflammatory signals in vascular endothelial cells (ECs). Here we examined the role of FKN in polarized Th1 or Th2 responses. Proinflammatory signals, including LPS, IL-1, TNF, and CD40 ligand, induced FKN, as did IFN-γ, which had synergistic activity with TNF. IL-4 and IL-13 did not stimulate the expression of FKN and markedly reduced induction by TNF and IFN-γ. TNF alone or combined with IFN-γ also induced release of soluble FKN, which was inhibited by IL-4 and IL-13. In light of this differential regulation of FKN by the master cytokines that control polarized responses, we analyzed the interaction of FKN with natural killer (NK) cells and polarized T-cell populations. NK cells expressed high levels of the FKN receptor CX3CR1 and responded to FKN. CX3CR1 was preferentially expressed in Th1 compared with Th2 cells. Th1 but not Th2 cells responded to FKN. By immunohistochemistry, FKN was expressed on ECs in psoriasis, a Th1-dominated skin disorder, but not in Th2-driven atopic dermatitis. Similarly, ECs in Mycobacterium tuberculosis granulomatous lymphadenitis, but not those in reactive lymph node hyperplasia or in Castelman's disease, showed immunoreactive FKN. These results indicate that regulated expression of FKN in ECs participates in an amplification circuit of polarized type I responses

Enhanced Recruitment of CX3CR1+ T Cells by Mucosal Endothelial Cell–Derived Fractalkine in Inflammatory Bowel Disease

“…Immunoregulatory cytokines can downregulate excessive chemokine production by endothelial cells, as documented by the ability of IL-4 and IL-13 to inhibit FKN production by human umbilical vein endothelial cells 18 . Surprisingly, this did not occur when IBD HIMEC were exposed to IL-4 or IL-10.…”

The chemokine system: tuning and shaping by regulation of receptor expression and coupling in polarized responses

“…Conversely, interferon(IFN)-c as expected inhibits production of CCL22/ MDC in different cell types and induces expression of CXCR3 agonists (3)(4)(5), as well as of CX3CL1/fractalkine. CX3CL1/fractalkine expression, the last identified chemokine involved in polarized responses (23), is induced by IFN-c and tumor necrosis factor (TNF) and inhibited by IL-4 and IL-13. Hence, using CCL22/MDC as a paradigm, this chemokine is induced by generic stimuli representatives of interaction with microbial pathogen lipopolysaccharide (LPS) or immunocompetent cells (CD40L).…”

Human fractalkine mediates leukocyte adhesion but not capture under physiological shear conditions; a mechanism for selective monocyte recruitment

“…However, it is the membrane-bound form that has generated the most interest as it potentially combines the direct action of an adhesion molecule with the specificity of a chemokine. Membrane-bound fractalkine is highly expressed in a number of murine models of inflammatory disease including cardiac allograft rejection [19], crescentric glomerulonephritis [20], and experimental autoimmune encephalomyelitis [21,22], as well as in the human inflammatory diseases rheumatoid arthritis [23], psoriasis [24] and atherosclerosis [25]. It is therefore very important to understand the mechanisms by which this chemokine may contribute to disease processes.…”