Evaluation of SOCS1 mimetic and antagonist peptides as therapeutic agents (P5152)

Abstract

The intracellular protein Suppressors of Cytokine Signaling1 (SOCS1) plays a critical role in moderating inflammatory cytokine signaling, thereby limiting immune responsiveness. We have shown that a peptide with the kinase inhibitory region of SOCS1 (SOCS1-KIR) inhibits Experimental Autoimmune Encephalomyelitis and rescues SOCS1-deficient mice from perinatal lethality. In contrast, a SOCS1antagonist pJAK2 enhances antiviral immunity to poxviruses. Therefore it is likely that peptides that modulate SOCS1 signaling possess the potential to modulate immune responses, and restore immune homeostasis. To evaluate the translational potential of SOCS1 mimetic peptides, we have assessed their pharmacodynamics by fluorescently labeling the peptides followed by injection into C57BL/6 mice. After 2 hours mice receiving Alexa 647 fluorochrome-conjugated SOCS1-KIR or pJAK2 were sacrificed, and subsequently whole organs and tissue histology were examined for the presence of the labeled peptides. We observed that pJAK2 and SOCS1-KIR were present in the brain, liver, lymph nodes, spleen, kidneys, lungs, and peritoneal cells. Notably, pJAK2 was selectively present within the thymus and heart. On a cellular level, SOCS1-KIR and pJAK2 were differentially present within CD4+ T cells, CD8+ T cells, CD11b+ macrophages, and B cells. These results help to lay the groundwork for the translational use of peptides that modulate SOCS signaling to regulate and/or maintain immune system homeostasis.