The p38 mitogen-activated protein kinase (MAPK) pathway in rheumatoid arthritis

Abstract

Chronic inflammatory processes are based on a sustained and tightly regulated communication network among different cells types. This network comprises extracellular mediators such as cytokines, chemokines and matrix-degrading proteases, which orchestrate the participation of cells in the chronic inflammatory process. The mirrors of this outside communication world are intracellular transcription factor pathways, which shuttle information about inflammatory stimuli to the cell nucleus. This review examines the function of one key signal transduction pathway of inflammation--the p38 mitogen-activated protein kinases (p38MAPK). The signalling pathway is considered as crucial for the induction and maintenance of chronic inflammation, and its components thus emerge as interesting molecular targets of small molecule inhibitors for controlling inflammation. This review not only summarises the current knowledge of activation, regulation and function of the p38MAPK pathway but also examines the role of this pathway in clinical disease. It gives an overview of current evidence of p38MAPK activation in inflammatory arthritis and elaborates the key molecular determinants which contribute to p38MAPK activation in joint disease.

Figure 1

Scheme of p38 mitogen-activated protein kinase (p38MAPK) activation. As a key intracellular signal transduction pathway the p38MAPK cascade links the plasma membrane (left) with the DNA (right). After activation of small GTPases (level 1), the signal is transduced by a three-step MAPK cascade (levels 2–4) before activating transcription factors (level 5).

Figure 2

Mitogen-activated protein kinase kinase kinases (MAPKKK) expression in rheumatoid arthritis (RA). (A, B) Immunostaining of the MEKK2, a MAPKKK in the synovial membrane of RA. The image depicts the lining layer and part of the synovial sublining. The lining layer shows intense pink staining for MEKK2 (A) but not with control immunoglobulin (B). (C) Immunoblots of cultivated synvovial findroblasts showing expression of the three different MAPKKK, MEKK3, TAK1 and MEKK3.

Figure 3

The role of MKK3 in arthritis. Mice deficient for MKK3 (MKK3−/−) are almost completely resistant to the serum transfer model of arthritis. (A) Course of joint swelling in wild-type (WT) and MKK3−/− mice induced for arthritis. (B) Microphotograph of histological sections of hind paws of WT and MKK3−/− mice challenged by arthritogenic serum.

Figure 4

Activation of p38 mitogen-activated protein kinase (p38MAPK) in rheumatoid arthritis. Activation of p38MAPK dominates in the synovial lining layer (SLL) and in endothelial cells (EC) of synovial microvessels. In contrast, the synovial sublining (SSL) and the perivascular regions (PV) are not major points of p38MAPK activation.

Figure 5

Expression and activation of p38 mitogen-activated protein kinase (p38MAPK) isoforms in rheumatoid arthritis (RA). (A) Immunoblot for p38MAPK isoforms in synovial tissue extracts from patients with RA. Individual patients differ in their patterns of MAPK isoform activation. (B, C) Microphotographs of synovial microvessels stained for phosphorylated p38MAPK (brown) and p38MAPKγ (B, green) or p38MAPKδ (C, green).

Figure 6

Function of p38 mitogen-activated protein kinase (p38MAPK) activation in rheumatoid arthritis. Activation of p38MAPK regulates mechanisms of endothelial cell function (A), synovial inflammation (B) and bone and cartilage degradation (C). Thus, p38MAPK is involved in the rolling, activation and chemoattraction of leucocytes as well as angiogenesis. In synovial inflammation, p38MAPK is important for proinflammatory cytokine expression, oxidation processes, activation of granulocytes and cell cycle regulation. The role of p38MAPK in cartilage and bone destruction is based on its role to induce matrix metalloproteinases and activation of osteoclasts. iNOS, inducible nitric oxide synthetase.