The expression of IL-28, a T-cell autocrine factor, is dysregulated in patients with SLE, supporting the possibility that IL-28 may contribute to some of the SLE pathogenesis.

Being expressed in immune cells, cytokine-inducible SH2 protein (CIS) and suppressors of cytokine signaling proteins, SOCS1, SOCS2 and SOCS3, can regulate cytokine signaling and immune responses. To evaluate the possible expressional dysregulation of CIS, SOCS1, SOCS2 and SOCS3 in systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) patients, the transcript levels of these genes in peripheral blood mononuclear cells (PBMCs) from SLE and RA patients were determined and statistically compared with those in PBMCs from normal individuals. It was found that SLE patients with the active disease activity significantly express higher CIS transcript levels than normal individuals and SLE patients with the inactive disease activity, whereas the difference in SOCS1, SOCS2 and SOCS3 transcript levels between normal individuals and SLE patients is not statistically significant. However, transcript levels of these CIS/SOCS genes in RA patients were not significantly different from those in normal individuals, except that treatment with a TNF-alpha-blocking agent in RA patients appears to enhance the CIS transcript expression, but down-regulates the SOCS2 transcript expression in PBMCs. These data suggest that CIS can serve as an SLE disease marker and may be involved in the pathogenesis of SLE, and that TNF-alpha may play an important role in the regulation of CIS and SOCS2 gene expression in PBMCs in vivo.

Toll-like receptor (TLR) activation and cytokines have been linked to the disease flare of systemic lupus erythematosus (SLE), yet the expression profiles of TLRs and cytokines in response to TLR activation in SLE patients remain unclear. In this study, we evaluated the expression levels of IL-10, TNF-α, interferon-γ (IFN-γ), TLR-2, TLR-4, and TLR-9 in peripheral blood mononuclear cells (PBMCs) from SLE patients and normal controls after PBMCs were stimulated with a TLR-2, TLR-4, or TLR-9 agonist. The expression levels in SLE patient group were statistically compared with those in normal control group. It was found in SLE patients that the IL-10 protein production was down-regulated after the activation of TLR-2, TLR-4, or TLR-9 and that the TNF-α protein production was decreased after the activation of TLR-2 or TLR-9, but not TLR-4. However, the transcript levels of IL-10 and TNF-α as well as the protein and transcript levels of IFN-γ were comparable between SLE and normal control groups. In addition, the TLR-2 transcript levels seem to be diminished after the activation of TLR-2, TLR-4, or TLR-9, but TLR-4 and TLR-9 transcript levels were not altered. The results indicate that the cytokine production from PBMCs in response to TLR activation is dysregulated in SLE patients, supporting the possibility that TLR activation may influence lupus disease activity through regulating cytokine production.

Platelet activation plays a major role in cardio and cerebrovascular diseases, and cancer progression. Disruption of platelet activation represents an attractive therapeutic target for reducing the bidirectional cross talk between platelets and tumor cells. Platinum (Pt) compounds have been used for treating cancer. Hence, replacing Pt with iridium (Ir) is considered a potential alternative. We recently developed an Ir(III)-derived complex, [Ir(Cp*)1-(2-pyridyl)-3-(2-hydroxyphenyl)imidazo[1,5-a]pyridine Cl]BF4 (Ir-11), which exhibited strong antiplatelet activity; hence, we assessed the therapeutic potential of Ir-11 against arterial thrombosis. In collagen-activated platelets, Ir-11 inhibited platelet aggregation, adenosine triphosphate (ATP) release, intracellular Ca2+ mobilization, P-selectin expression, and OH· formation, as well as the phosphorylation of phospholipase Cγ2 (PLCγ2), protein kinase C (PKC), mitogen-activated protein kinases (MAPKs), and Akt. Neither the adenylate cyclase inhibitor nor the guanylate cyclase inhibitor reversed the Ir-11-mediated antiplatelet effects. In experimental mice, Ir-11 prolonged the bleeding time and reduced mortality associated with acute pulmonary thromboembolism. Ir-11 plays a crucial role by inhibiting platelet activation through the inhibition of the PLCγ2–PKC cascade, and the subsequent suppression of Akt and MAPK activation, ultimately inhibiting platelet aggregation. Therefore, Ir-11 can be considered a new therapeutic agent against either arterial thrombosis or the bidirectional cross talk between platelets and tumor cells.