Cytokines and cytokine receptors as targets of immune-mediated inflammatory diseases-RA as a role model

Abstract

Recent advances in our understanding in the immune-mediated inflammatory diseases (IMID) are explored and promoted by the targeted treatment. Among these targets, cytokines and cytokine receptors have become the good candidates for the drug development. In this review, the cytokine and cytokine receptors, which are approved in IMID, are overviewed, and modalities of the treatment, the role of cytokines and cytokine receptors in each disease, and the updated molecular information by modern technologies in rheumatoid arthritis as a role model are shown and discussed for the future perspectives.

Keywords: Biological agents; Cytokine; Cytokine receptor; Immune-mediated inflammatory diseases; JAK inhibitors.

Fig. 1

Cytokines and cytokine receptor families involved in immune-mediated diseases. White boxes in the top part of the figure list the cytokines implicated in IMID, which bind the cytokine receptors schematically depicted below. Horizontal gray bar represents the cell membrane. Under the cell membrane, signaling systems located downstream of the cytokine receptors are indicated. Gray boxes on the right list biological agents located outside the cells (top) and JAK inhibitors located inside the cells (bottom)

Fig. 2

Structure of biological agents used to treat immune-mediated inflammatory diseases. Gray-colored regions in the chimeric and humanized antibodies indicate mouse proteins. #Approved in Japan for RA, *not approved in Japan, $not indicated for RA

Fig. 3

Working hypothesis of the hierarchical cytokine network in patients with RA. White boxes indicate cells. Light gray box indicates autoantibody. Dark gray boxes indicate targeted treatments and methotrexate (MTX). RF, rheumatoid factor; AMPA, anti-modified protein antibody; SL, sublining in synovial tissues; LL, lining in synovial tissues. *Not approved in Japan

Fig. 4

Hypothesized model of the molecular and cellular mechanisms underlying arthritis. Straw-colored region in the top part indicates joint fluid. Boxes enclosed by broken lines indicate the lining, sublining, bone, and bone marrow. Tissue-resident-protective macrophages [76] become activated and differentiate and move into the lining space. CX3CR1^low monocytes in the circulating blood produced in bone marrow migrate into the sublining space, where they become CXC3R1^high macrophages and produce cytokines and chemokines [77]. Some activated macrophages, stimulated by M-CSF, differentiate into precursors with FoxM1 and are designated arthritis-associated osteoclastogenic macrophages (AtoM) [78]. Boxes indicate cytokines and chemokines, and solid lines show their action on cellular targets. Broken lines show the shift or differentiation of a cell. Double-headed arrows indicate cellular interaction

Fig. 5

Pre-disease stage RA and RA [70]. The y-axis indicates the relative level of inflammation, and the x-axis indicates the relative time from the cause to the development of RA and the disease course after treatment