We previously reported the inhibitory action of interleukin-6 (IL-6) on B lymphopoiesis with SHIP ؊/؊ mice and showed that IL-6 biases lineage commitment toward myeloid cell fates in vitro and in vivo. Because elevated IL-6 is a feature of chronic inflammatory diseases, we applied an animal model of systemic lupus erythematosus (SLE) to determine whether IL-6 has similar effects on hematopoiesis. We found that IL-6 levels were elevated in the B6.Sle1.Yaa mice, and the increase was accompanied by losses of CD19 ؉ B cells and more primitive B-lymphoid progenitors in bone marrow. Both the CD19 ؉ B-cell population and their progenitors recovered in an IL-6 ؊/؊ background. The uncommitted progenitors, containing precursors for both lymphoid and myeloid fates, expressed IL-6 receptor-␣ chain and responded to IL-6 by phosphorylation of STAT3. IL-6 stimulation caused uncommitted progenitors to express the Id1 transcription factor, which is known to inhibit lymphopoiesis and elevate myelopoiesis, and its expression was MAPK dependent. We conclude that chronic inflammatory conditions accompanied by increased IL-6 production bias uncommitted progenitors to a myeloid fate by inducing Id1 expression. IntroductionAll hematopoietic cells develop from pluripotent hematopoietic stem cells (HSCs). Hematopoietic development proceeds in stages of decreasing lineage choices and decreasing capacity for selfrenewal of the progeny. HSCs feature a lack of all lineage markers (Lin Ϫ ) but express high levels of the receptor tyrosine kinase c-Kit (c-Kit hi ) and the surface protein Sca-1 (termed the LSK fraction). HSCs give rise to multipotent progenitors (MPPs), marked by a loss of self-renewal capacity, the ability to form either myeloid or lymphoid cells, and up-regulation of the Flk2/Flt3 receptor tyrosine kinase. 1 The earliest lymphoid-biased progenitors (ELPs) represent a subset of MPPs that can be resolved from all other progenitors on the basis of recombination activating gene 1 expression. 2 Lymphoid progenitors that develop from MPPs have reduced levels of c-Kit, display surface interleukin-7 receptor ␣ (IL-7R␣), and have other properties that define a population called common lymphoid progenitors (CLPs). 3 Hematopoiesis is normally a well-controlled system designed to replenish blood cells at a constant rate, such that the balance of lymphoid and myeloid cells is maintained. However, the rate of output of particular blood cell types can be altered by conditions such as leukemia, radiation, or acute inflammation. 4-11 One condition termed "emergency hematopoiesis," 12,13 is characterized by elevated production of myeloid cells, occurring during acute infections or acute allergic responses. The mechanism by which hematopoiesis is altered to elevate production of myeloid cells is not known. The consequence of emergency hematopoiesis is to increase circulating monocytes, granulocytes, and neutrophils, presumably present to fight infection.Interleukin-6 (IL-6) is a prominent cytokine produced during infectious disease (reviewed in...