Original Article

Modulation of the Nuclear Factor B Pathway by Shp-2 Tyrosine Phosphatase in Mediating the Induction of Interleukin (IL)-6 by IL-1 or Tumor Necrosis Factor

Correspondence to: Gen-Sheng Feng, The Burnham Institute, 10901 N. Torrey Pines Rd., La Jolla, CA 92037. Tel:858-713-6265 Fax:858-713-6274 E-mail:gfeng{at}burnham.org.

Shp-2, a src homology (SH)2-containing phosphotyrosine phosphatase, appears to be involved in cytoplasmic signaling downstream of a variety of cell surface receptors, although the mechanism is unclear. Here, we have determined a role of Shp-2 in the cytokine circuit for inflammatory and immune responses. Production of interleukin (IL)-6 in response to IL-1 or tumor necrosis factor (TNF)- was nearly abolished in homozygous mutant (Shp-2^-/-) fibroblast cells. The targeted Shp-2 mutation has no significant effect on the activation of the three types of mitogen-activated protein (MAP) kinases, extracellular signal-regulated kinase (Erk), c-Jun NH₂-terminal kinase (Jnk), and p38, by IL-1/TNF, indicating that Shp-2 does not work through MAP kinase pathways in mediating IL-1/TNF-induced IL-6 synthesis. In contrast, IL-1/TNF-stimulated nuclear factor (NF)-B DNA binding activity and inhibitor of B (IB) phosphorylation was dramatically decreased in Shp-2^-/- cells, while the expression and activity of NF-B–inducing kinase (NIK), Akt, and IB kinase (IKK) were not changed. Reintroduction of a wild-type Shp-2 protein into Shp-2^-/- cells rescued NF-B activation and IL-6 production in response to IL-1/TNF stimulation. Furthermore, Shp-2 tyrosine phosphatase was detected in complexes with IKK as well as with IL-1 receptor. Thus, this SH2-containing enzyme is an important cytoplasmic factor required for efficient NF-B activation. These results elucidate a novel mechanism of Shp-2 in cytokine signaling by specifically modulating the NF-B pathway in a MAP kinase–independent fashion.

Key Words: tyrosine phosphatase, IL-1, IL-6, TNF, Shp-2

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