Limitin: A New Cytokine Inhibitor of B-cell Development

Bone marrow stromal cells produce and express molecules required for hematopoietic stem cell survival, proliferation, differentiation and migration. For example, the bone marrow stromal-derived cell line BMS2 can promote growth of B-cell precursors.1 The BMS2.4 subclone of BMS2, however, produces a soluble growth inhibitor for several lympho-hematopoietic cell lines.2,3 BMS2.4 can specifically suppress the proliferation of several pre-B-cell lines and one myelomonocytic leukemia cell line. This inhibition is not due to TNF-alpha, TGF-beta or IFN-beta activity, but rather to the activity of a new cytokine, limitin.4

Limitin may represent a previously unknown type I interferon prototype. It has weak homology with IFN-alpha,5 IFN-beta6 and IFN-beta receptors and induction of IRF-1 expression suggests that it might have similar biological functions as other type I interferons.

Exposure of B-cell precursors and a myelomonocytic leukemia cell line to a limitin-Ig fusion protein specifically inhibits B-cell lymphopoiesis both in vitro and in vivo and also induces tyrosine phosphorylation of various Jak-Stat proteins.4 The two Jak tyrosine kinase family members, Jak1 and Tyk2, are involved in the IFN-alpha or IFN-beta induced signaling pathway by association with the two receptor subunits, IFNAR1 and IFNAR2.9-12 Limitin induces tyrosine phosphorylation of Jak1 and Tyk2 in B-cell precursors and Jak2 in a myelomonocytic leukemia cell line (see Figure 1).

Limitin may inhibit lympho-hematopoiesis through apoptosis, growth arrest, or interference with the establishment of adherent stromal cell layers.4 The lineage-specific growth inhibition is a unique feature of this cytokine. Questions still remain, however, regarding whether limitin-specific responses are mediated exclusively through IFN-a/b receptors, if there are other limitin receptors and/or if there are additional functions for limitin.

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