Table 1.
Main cytokines implicated in Graves’ ophthalmopathy, the cells producing them and their biological effects.
| Retrobulbar Cells | Main Cytokines | Biological effects | References |
|---|---|---|---|
| Fibroblasts/preadipocytes | IFN-γ, TNF-α, IL-1α has been observed in tissue sections and in primary OF cultures of patients with active GO | IFN-γ, TNF-α, IL-1α in fibroblast stimulate: -the expression of a 72-kDa heat shock protein (HSP 72) -the expression of inter-cellular adhesion molecule-1 (ICAM-I). IFN-γ, TNF-α enhance the expression of HLA-DR |
(50) |
| IL-6, 8, 16, RANTES, MCP-1, IFN-γ, TNF-α, IL-1 | IL-16 acts as a ligand for CD4+ cells, and it is important for T-cell trafficking. IL-16 production is believed to follow that of RANTES, and both are responsible for T-cell trafficking in orbital and thyroid fibroblasts | (51) | |
| In retrobulbar fibroblasts and preadipocytes obtained from GO patients: 1)IFN-γ induced CXCL10 secretion in a dose-dependent manner; 2)TNF-α alone was not able to induce chemokine secretion; 3)IFN-γ+TNF-α synergistically increased CXCL10 secretion |
CXCL10 induces the migration of Th1 lymphocytes into the orbit, thereby perpetuating the autoimmune cascade | (52, 53) | |
| In retrobulbar fibroblasts and preadipocytes obtained from GO patients: 1) IFN-γ alone dose dependently induced the secretion of CXCL9 and CXCL11; 2) IFN-γ+TNF-α combination leads to a huge response of CXCL9 |
C-X-C chemokines participate in the self-perpetuation of inflammation | (54) | |
| -Cytokines detected in situ in GO include TNF-α, IL-1α, IL-6, IL-8, IL-10, IL-12, IL-13, and IFN-γ; -Several of these are more highly expressed in active vs stable disease and include IL-1β, IL-6, IL-8, and IL-10; -predominance of T helper (Th)1 cytokines in active GO |
-Both IFN-γ and TNF-α induce B cell activating factor in GD OF -IL-1β induces both IL-16 and RANTES in GD OF, enhancing the release of T cell migration-promoting activity |
(55) | |
| In cultured primary OF from GO patients: -IL-17A combined with CD40L could induce the production of RANTES in time- and dose-dependent modifications; -IL-17A alone was not enough sufficient to trigger RANTES release |
Amplification of GO inflammatory process | (56) | |
| In primary cell cultures of GO fibroblasts and preadipocytes: 1)TNF-α increases the secretion of CXCL8 dose-dependently; 2) IFN-γ stimulates the secretion of CXCL10, but it inhibits that of CXCL8 |
This differential modulation of CXCL10 and CXCL8 chemokines could reflect a different role of the two chemokines during the course of the disease, as CXCL10 could be associated with the initial phase of the disease when a Th1 immune response (induced by IFN-γ) is preponderant, while CXCL8 could be associated with a later chronic phase of the disease, when there is a switch to a Th2 prevalent immune response (induced by TNF-α) | (57) | |
| Adipocytes | High levels of MCP-1 mRNA in the orbital fat tissue of patients with GO have been reported | MCP-1 positively correlated with the degree of macrophage infiltration in patients with GO | (58) |
| Muscle cells | In primary extraocular muscle
(EOM) cultures from patients with GO: 1)IFN-γ induced CXCL10 secretion in a dose-dependent manner; 2)IFN-γ+TNF-α synergistically increased CXCL10 secretion; 3)IFN-γ and TNF-α induce CCL2 secretion |
Self-perpetuation of inflammation | (59) |
GO, Graves’ ophthalmopathy; IP-10, IFN-γ-inducible protein 10;C-X-C motif (CXCL)10, chemokine ligand 10; IFN-γ, interferon-γ; IL, interleukin; MCP-1/CCL2, monocyte chemoattractant protein-1; OF, orbital fibroblasts; TNF-α, tumor necrosis factor-α.