The activation of STAT3 by tyrosine phosphorylation, essential for normal development and for a normal inflammatory response to invading pathogens, is kept in check by negative regulators. Abnormal constitutive activation of STAT3, which contributes to the pathology of cancer and to chronic inflammatory diseases such as rheumatoid arthritis, occurs when negative regulation is not fully effective. SOCS3, the major negative regulator of STAT3, is induced by tyrosine-phosphorylated STAT3 and terminates STAT3 phosphorylation about 2 h after initial exposure of cells to members of the IL-6 family of cytokines by binding cooperatively to the common receptor subunit gp130 and JAKs 1 and 2. We show here that when the epidermal growth factor receptor (EGFR) is present and active, STAT3 is rephosphorylated about 4 h after exposure of cells to IL-6 or oncostatin M and remains active for many hours. Newly synthesized IL-6 drives association of the IL-6 receptor and gp130 with EGFR, leading to EGFR-dependent rephosphorylation of STAT3, which is not inhibited by the continued presence of SOCS3. This second wave of STAT3 activation supports sustained expression of a subset of IL-6-induced proteins, several of which play important roles in inflammation and cancer, in which both IL-6 secretion and EGFR levels are often elevated.A fter ligand-induced dimerization of the IL-6 receptor (IL-6R), the associated kinases JAK1 and JAK2 cross-phosphorylate tyrosine residues of adjacent glycoprotein 130 (gp130) subunits of the complex. The SH2 domain of STAT3 binds to newly phosphorylated tyrosines, followed by the phosphorylation of Y705 of STAT3 (1). Two phosphorylated STAT3 monomers then dimerize and translocate to the nucleus,

It has been shown that proinflammatory and antiinflammatory cytokines correlate with disease activity in multiple sclerosis (MS). To establish whether such correlations depend on the disease stage, we assessed in a longitudinal fashion the expression of interleukin (IL)‐12 (p40 and p35), tumor necrosis factor‐α, interferon‐γ, and IL‐10 mRNA by competitive polymerase chain reaction in unstimulated peripheral blood mononuclear cells of relapsing–remitting (RR) and secondary progressive (SP) MS patients, in relation to monthly clinical and magnetic resonance imaging monitoring. MS patients had increased levels of IL‐12p40 and decreased levels of IL‐10 mRNA compared with controls; this difference was most pronounced in SP patients. Both RR and SP patients had increased levels of IL‐12p40 mRNA compared with controls during the development of active lesions. Moreover, in RR MS an increase was found before relapse. IL‐12p35 mRNA was decreased in both groups, and in relation to disease activity it showed a pattern different from IL‐12p40 mRNA. In RR MS, IL‐10 mRNA was low 4 weeks before magnetic resonance imaging activity and 6 weeks before relapse; a significant increase to normal levels was noted when active lesions became apparent. In contrast, SP patients showed low IL‐10 mRNA levels constitutively, suggesting that IL‐10 plays an important role in the control of disease progression. Ann Neurol 1999;45:695–703

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Interferon (IFN)‐β treatment is effective in relapsing‐remitting multiple sclerosis (RR‐MS) via an as yet unidentified mechanism. In the present study, we investigated whether the expression of messenger RNA (mRNA) encoding the interleukin (IL)‐12 subunits p40 and p35, IL‐12 receptor chains, IL‐18, tumor necrosis factor‐α (TNFα), IFNγ, IL‐10, IL‐4, or transforming growth factor‐β in unstimulated whole blood of 26 RR‐MS patients changed during 6 months of IFNβ‐1b treatment. In these patients, a significant change was found in TNFα mRNA, whereas changes in IL‐12 receptor‐β2 and IL‐10 mRNA showed a trend. IFNβ‐1b–related changes in cytokine mRNA expression were next evaluated in clinical subgroups of RR‐MS patients classified as either clinical responders or nonresponders on the basis of Expanded Disability Status Scale progression and the number of relapses and steroid interventions needed in the 2 years before initiation of treatment compared with the 2 years after initiation of treatment. These subgroups showed different response patterns to IFNβ‐1b treatment with respect to IL‐10, TNFα, and IL‐18 only. Surprisingly, clinical responders displayed no change in these cytokines, whereas nonresponders showed a decrease in TNFα and IL‐18 mRNA as well as a transient increase in IL‐10 mRNA. Baseline levels of IL‐12p35 mRNA were lower in the responders compared with the nonresponders: this marker correctly predicted the clinical outcome in 81% of the 26 patients under investigation. Ann Neurol 2000;48:313–322

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