THE IMMUNOBIOLOGY OF CARCINOGENESIS (EVANS)

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The pathogenic basis for the dramatic and characteristic tissue remodeling associated with the autoimmuine disease Graves' ophthalmopathy most likely resides in the interaction of fibroblasts with immunocompetent cells, including B and T lymphocytes, mast cells and monocytes. Once trafficked to the orbit these cells apparently initiate processes leading to fibroblast activation and the accumulation of hyaluronan. It is the profound hydrophilicity of hyaluronan that results in the partial extrusion of orbital contents and the manifestation of proptosis. Leukoregulin, a 50 kiloDalton anti-cancer cytokine secreted by lymphocytes, can increase hyaluronan synthesis by greater than 15-fold in orbital fibroblasts. The magnitude of this increase is unprecedented in mammalian cell systems and implicates leukoregulin as a candidate molecular trigger in the activation of orbital fibroblasts in Graves' ophthalmopathy. Another striking feature of the active phase of ophthalmopathy is an intense inflammatory reaction. Leukoregulin dramatically increases prostaglandin E2 (PGE2) synthesis in orbital fibroblasts; this up-regulation is mediated through an induction of prostaglandin-endoperoxide H synthase-2 (PGHS-2), the inflammatory cycoloxygenase. The increased PGHS-2 expression elicited by leukoregulin in orbital fibroblasts may be a consequence of both transcriptional and post-transcriptional effects. These observations help clarify the pathogenic mechanisms relevant to the intense inflammation associated with Graves' ophthalmopathy. Lymphocytes trafficked to orbital tissues have a putative role, through the cytokines they release, in the activation of fibroblasts in this autoimmune disease. The heightened sensitivity of orbital fibroblasts to the differential gene regulatory action of leukoregulin, moreover, is reminiscent of the response of cervical carcinoma, leukemia and other tumor cells to this cytokine. Orbital fibroblasts, therefore, may provide a unique new resource for the study of cytokine responsive tumor cell properties and markers.