The Role of Interleukin-4 and Interleukin-10 in Osteoarthritic Joint Disease: A Systematic Narrative Review

Abstract

Objective: A fusion protein of interleukin-4 and interleukin-10 (IL4-10 FP) was developed as a disease-modifying osteoarthritis drug (DMOAD), and chondroprotection, anti-inflammation, and analgesia have been suggested. To better understand the mechanisms behind its potential as DMOAD, this systematic narrative review aims to assess the potential of IL-4, IL-10 and the combination of IL-4 and IL-10 for the treatment of osteoarthritis. It describes the chondroprotective, anti-inflammatory, and analgesic effects of IL-4, IL-10, and IL4-10 FP.

Design: PubMed and Embase were searched for publications that were published from 1990 until May 21, 2021 (moment of search). Key search terms were: Osteoarthritis, Interleukin-4, and Interleukin-10. This yielded 2,479 hits, of which 43 were included in this review.

Results: IL-4 and IL-10 showed mainly protective effects on osteoarthritic cartilage in vitro and in vivo, as did IL4-10 FP. Both cytokines showed anti-inflammatory effects, but also proinflammatory effects. Only in vitro IL4-10 FP showed purely anti-inflammatory effects, indicating that proinflammatory effects of one cytokine can be counteracted by the other when given as a combination. Only a few studies investigated the analgesic effects of IL-4, IL-10 or IL4-10 FP. In vitro, IL-4 and IL4-10 FP were able to decrease pain mediators. In vivo, IL-4, IL-10, and IL4-10 FP were able to reduce pain.

Conclusions: In conclusion, this review describes overlapping, but also different modes of action for the DMOAD effects of IL-4 and IL-10, giving an explanation for the synergistic effects found when applied as combination, as is the case for IL4-10 FP.

Keywords: interleukins; osteoarthritis; osteoarthritis disease modification.

Figure 1.

Expression of IL-4, IL-10, and their receptors (IL-4R and IL-10R) in the healthy and osteoarthritic joint. Created by Biorender.com. In healthy joints, IL-4, IL-10, and their receptors IL-4R and IL-10R are found in multiple joint tissues.^,- In OA, chondrocytes express more IL-10 and receptors for IL-10 and IL-4 (IL10R, IL4R).^, In contrast, the expression of IL-4 is less in OA cartilage compared with normal cartilage. The OA synovium is infiltrated by multiple inflammatory cells, increasing the expression of IL-4 (e.g., produced by Th2 cells) and IL-10 (e.g., produced by B-cells), and IL-4R is found in lymphocyte aggregates. IL-4 = interleukin-4; IL-10 = interleukin-10; IL-4R = IL-4 receptor; IL-10R = IL-10 receptor; OA = osteoarthritis.

Figure 2.

Selection process. OA = osteoarthritis; IL-4 = interleukin-4; IL-10 = interleukin-10.

Figure 3.

DMOAD effects of IL-4. Created by Biorender.com. ↓ = reduction; ↑ = increase; ↓/↑ = different results; C2C = collagen type II C-terminal cleavage neoepitope; DMOAD = disease-modifying osteoarthritis drug; ADAMTS = A desintegrin and metalloproteinase with thrombospondin motifs; MMP = matrix metalloproteinase; CITED-2 = Cbp/P300 interacting transactivator with Glu/Asp-rich carboxy terminal domain 2; COMP = cartilage oligomeric matrix protein; PGE₂ = prostaglandin E₂; TNFα = tumor necrosis factor-alpha; COX-2 = cyclooxygenase-2; mPGES-1 = microsomal prostaglandin E synthase-1; NO = nitric oxide; NOS2 = nitric oxide synthase-2; IL = interleukin; IFNγ = interferon gamma; IGF-1 = insulin growth factor-1; TGFβ = tumor growth factor-beta; CCL = chemokine (C-C motif) ligand; ICAM-1 = intercellular adhesion molecule-1; MCP-1 = monocyte chemoattractant protein-1; Scn3a = sodium voltage–gated channel alpha subunit 3 coding gene; Trpv1 = transient receptor potential cation channel subfamily V member 1 coding gene; PWT = paw-withdrawal threshold.

Figure 4.

DMOAD effects of IL-10. Created by Biorender.com. ↓ = reduction; ↑ = increase; ↓/↑ = different results; ADAMTS = A desintegrin and metalloproteinase with thrombospondin motifs; DMOAD = disease-modifying osteoarthritis drug; MMP = matrix metalloproteinase; SOX9 = transcription factor sox 9 coding gene; PGE₂ = prostaglandin E₂; TNFα = tumor necrosis factor-alpha; COX-2 = cyclooxygenase-2; NO = nitric oxide; NOS2 = nitric oxide synthase-2; IL = interleukin; IFNγ = interferon gamma; (s)HLA-G = (soluble) human leukocyte antigen G; TGFβ = tumor growth factor-beta; SOCS = suppressor of cytokine signaling; PWL = paw-withdrawal latency; PWT = paw-withdrawal threshold; DRG = dorsal root ganglia.

Figure 5.

DMOAD effects of IL4-10 fusion protein. Created by Biorender.com. ↓ = reduction; ↑ = increase; ↓/↑ = different results; DMOAD = disease-modifying osteoarthritis drug; MMP = matrix metalloproteinase; IL = interleukin; TNFα = tumor necrosis factor-alpha; VEGF = vascular endothelial growth factor; IGF = insulin growth factor; PWT = paw-withdrawal threshold.