The SOCS (suppressors of cytokine signaling) proteins have been suggested to function as inhibitors of cytokine receptor signaling. We have analyzed SOCS-2, SOCS-3, and CIS expression in relation to GH actions in the rat. SOCS-2, SOCS-3, and CIS transcripts were detected in various GH responsive tissues, including liver, muscle, and fat. In addition to the finding that different tissues express different levels of SOCS-2, SOCS-3, and CIS messenger RNA (mRNA), the steady-state levels of these SOCS transcripts were dependent on the endocrine status of the animal. SOCS-3 expression was 5-fold higher in fat from old compared with younger rats. Hypophysectomy reduced the levels of SOCS-2 and CIS mRNA in liver, muscle, and fat, whereas SOCS-3 expression was unchanged. Using primary cultures of rat hepatocytes, GH was shown to increase SOCS-2, SOCS-3, and CIS mRNA levels with different kinetics. SOCS-3 was rapidly and transiently induced, whereas SOCS-2 and CIS were increased in a slower fashion. Glucocorticoids blocked GH-induced SOCS-3 expression in cultured hepatocytes, whereas SOCS-2 and CIS expression was potentiated. Our data fit well with a concept of SOCS proteins acting as modulators of GH signal transduction.