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

Fractalkine (FKN, CX3CL1) is a membrane-bound CX3C chemokine induced by pri mary proinflammatory signals in vascular endothelial cells (ECs). Here we e xamined 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 -gamma, which had synergistic activity with TNF. IL-4 and IL-13 did not sti mulate the expression of FKN and markedly reduced induction by TNF and IFN- gamma. TNF alone or combined with IFN-gamma 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 pola rized T-cell populations. NK cells expressed high levels of the FKN recepto r CX3CR1 and responded to FKN. CX3CR1 was preferentially expressed in Th1 c ompared with Th2 cells. Th1 but not Th2 cells responded to FKN. By immunohi stochemistry, FKN was expressed on ECs in psoriasis, a Th1-dominated skin d isorder, but not in Th2-driven atopic dermatitis. Similarly, ECs in Mycobac terium 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 participat es in an amplification circuit of polarized type I responses.