Cish knockout mice exhibit similar outcomes to malaria infection despite altered hematopoietic responses.

The Cytokine-inducible Src homology 2 domain-containing (CISH) protein is a negative feedback regulator induced by cytokines that play key roles in immunity and erythropoiesis. Single nucleotide polymorphisms (SNPs) in the human CISH gene have been associated with increased susceptibility to severe malaria disease. To directly assess how CISH might influence outcomes in the BALB/c model of malaria anemia, CISH knockout (Cish-/-) mice on this background were infected with Plasmodium berghei and their hematopoietic responses, cytokine production and ability to succumb to severe malaria disease evaluated. Despite basal erythrocytic disruption, upon P. berghei infection, the Cish -/- mice were better able to maintain peripheral blood cell counts, hemoglobin levels and a steady-state pattern of erythroid differentiation compared to wild-type (Cish+/+) mice. Ablation of CISH, however, did not influence the outcome of acute malaria infections in either the BALB/c model or the alternative C57BL/6 model of experimental cerebral malaria, with the kinetics of infection, parasite load, weight loss and cytokine responses being similar between Cish+/+ and Cish-/- mice, and both genotypes succumbed to experimental cerebral malaria within a comparable timeframe.

Role of Cytokine-Inducible SH2 Domain-Containing (CISH) Protein in the Regulation of Erythropoiesis.

The cytokine-inducible SH2 domain-containing (CISH) protein was the first member of the suppressor of cytokine signaling (SOCS) family of negative feedback regulators discovered, being identified in vitro as an inducible inhibitor of erythropoietin (EPO) signaling. However, understanding of the physiological role played by CISH in erythropoiesis has remained limited. To directly assess the function of CISH in this context, mice deficient in CISH were characterized with respect to developmental, steady-state, and EPO-induced erythropoiesis. CISH was strongly expressed in the fetal liver, but CISH knockout (KO) mice showed only minor disruption of primitive erythropoiesis. However, adults exhibited mild macrocytic anemia coincident with subtle perturbation particularly of bone marrow erythropoiesis, with EPO-induced erythropoiesis blunted in the bone marrow of KO mice but enhanced in the spleen. Cish was expressed basally in the bone marrow with induction following EPO stimulation in bone marrow and spleen. Overall, this study indicates that CISH participates in the control of both basal and EPO-induced erythropoiesis in vivo.

The Role of Cytokine-Inducible SH2 Domain-Containing Protein (CISH) in the Regulation of Basal and Cytokine-Mediated Myelopoiesis.

Cytokine-inducible SH2 domain-containing protein (CISH) is a member of the suppressor of cytokine signaling (SOCS) family of negative feedback regulators shown to play crucial roles in lymphoid cell development and function as well as appetite regulation. It has also been implicated in the control of signaling downstream of the receptors for the cytokines granulocyte/macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF) in myeloid cells. To investigate the physiological role of CISH in myelopoiesis, mice deficient in CISH were analyzed basally and in response to administration of these cytokines. CISH knockout (KO) mice possessed basally elevated neutrophils in the blood, bone marrow, and spleen compared to wild-type (WT) mice. During GM-CSF-induced myelopoiesis, the frequency of neutrophils, myeloid dendritic cells (DCs), and CFU-M in the bone marrow was higher in the KO, as were the neutrophils and CFU-G in the spleen. In contrast, no differences were observed between KO and WT mice during G-CSF-induced myelopoiesis apart from an elevated frequency of CFU-G and CFU-M in the spleen. This work has identified a role for CISH in the negative regulation of granulopoiesis, including that mediated by GM-CSF.

Cytokine-inducible SH2 domain containing protein contributes to regulation of adiposity, food intake, and glucose metabolism.

The cytokine-inducible SH2 domain containing protein (CISH) is the founding member of the suppressor of cytokine signaling (SOCS) family of negative feedback regulators and has been shown to be a physiological regulator of signaling in immune cells. This study sought to investigate novel functions for CISH outside of the immune system. Mice deficient in CISH were generated and analyzed using a range of metabolic and other parameters, including in response to a high fat diet and leptin administration. CISH knockout mice possessed decreased body fat and showed resistance to diet-induced obesity. This was associated with reduced food intake, but unaltered energy expenditure and microbiota composition. CISH ablation resulted in reduced basal expression of the orexigenic Agrp gene in the arcuate nucleus (ARC) region of the brain. Cish was basally expressed in the ARC, with evidence of co-expression with the leptin receptor (Lepr) gene in Agrp-positive neurons. CISH-deficient mice also showed enhanced leptin responsiveness, although Cish expression was not itself modulated by leptin. CISH-deficient mice additionally exhibited improved insulin sensitivity on a high-fat diet, but not glucose tolerance despite reduced body weight. These data identify CISH as an important regulator of homeostasis through impacts on appetite control, mediated at least in part by negative regulation of the anorexigenic effects of leptin, and impacts on glucose metabolism.