Preferred Label : NO2-Dependent IL12 Pathway;
NCIt related terms : NO2-dependent IL 12 Pathway in NK cells;
Alternative definition : BIOCARTA: Macrophages and NK cells help provide innate immunity against infection
by intracellular parasites and communicate with each other to regulate this process.
When stimulated, macrophages secrete the cytokine IL-12 which is essential for activation
of the cytotoxic activity of natural killer (NK) cells. IL-12 stimulates this NK cell
response through activation of a JAK/STAT signaling pathway. Binding of IL-12 to its
receptor on NK cells causes tyrosine phosphorylation and activation of JAK2 and another
JAK kinase, Tyk2. Tyk2 in turn phosphorylates the transcription factor STAT4, which
can then translocate to the nucleus to activate genes, including the expression of
interferon-gamma. IFN-gamma and IL-12 induce the differentiation of TH1 helper T cells
that activate macrophages through interferon-gamma. A key modulator of NK cell activation
by IL-12 is nitric oxide, NO, produced from arginine by the inducible nitric oxide
synthase NOS2. Inactivation of the NOS2 gene in mice impairs the initial innate response
to infection, including the activation of NK cells. This phenotype is similar to that
of mice lacking interferon-gamma or IL-12 and a similar effect can be produced by
inhibiting NOS2 with L-N6-iminoethyl-lysine (L-NIL) during infection, blocking the
activation of NK cells by IL-12. NO production does not affect the activation of JAK2
by IL-12, but is required for Tyk2 activity, the downstream activation of STAT-4 and
the production of interferon-gamma by NK cells. The role of NO in Tyk2 activation
is not yet known, but does not seem to involve changing the phosphorylation status
of Tyk2. Curiously, activation of T cells by IL-12 does not appear to involve NO production,
indicating a distinct mechanism is involved in NK cells. NO also plays a role as a
feedback inhibitor of IL-12 production by macrophages, helping to prevent over-activation
of the Th1 cells by IL-12. NO appears to make an important contribution to the early
innate response to infections before specific immunity is active. (This definition
may be outdated - see the DesignNote.);
NCIt note : The BIOCARTA Definition (ALT_DEFINITION) for this pathway concept was provided by
BioCarta. This property was not created by, nor is it maintained by the NCI Thesaurus
staff. Additionally, BioCarta is no longer updating its pathway data; thus, the BIOCARTA
Definition might be outdated or inaccurate. Please see the Terms and Conditions for
Use at http://www.biocarta.com/.;
Biocarta ID : h_no2il12Pathway;
Origin ID : C39168;
UMLS CUI : C1513847;
Semantic type(s)
- has_gene_product_element
- pathway_has_gene_element
