Paracrine, juxtacrine, and autocrine stimuli (column a) and effector molecules (column b) of macrophage (Mφ) activation in rheumatoid arthritis. Most of the regulatory products of activated macrophages act on macrophages themselves, creating autocrine regulatory loops whose dysregulation possibly promotes disease severity and chronicity. The jagged arrow in the T cell indicates the necessity of pre-activating T cells for effective juxtacrine stimulation of macrophages. AP-1, activation protein; EC, endothelial cells; FB, fibroblasts; ICAM, intracellular adhesion molecule; IL, interleukin; IL-1RA, interleukin-1 receptor antagonist; LFA-3, lymphocyte function-associated antigen-3; MIF, migration inhibitory factor; mTNF-α, mouse tumor necrosis factor-alpha; NF-κB, nuclear factor-kappa-B; NK, natural killer cells; sTNF-R, soluble tumor necrosis factor receptor; TGF-β, transforming growth factor-beta; TNF-α, tumor necrosis factor-alpha; VCAM-1, vascular cell adhesion molecule-1. Reproduced with permission from Kinne RW, Stuhlmuller B, Palombo-Kinne E, Burmester GR: The role of macrophages in rheumatoid arthritis. In Rheumatoid Arthritis. Edited by Firestein GS, Panayi GS, Wollheim FA. New York: Oxford University Press; 2006:55–75 .