TNF-alpha is associated with the development of interstitial fibrosis. We have demonstrated that the p38 mitogen-activated protein (MAP) kinase regulates TNF-alpha expression in monocytes exposed to asbestos. In this report, we asked if extracellular signal-regulated kinase (ERK) was also involved in TNF-alpha expression in monocytes exposed to asbestos. We found that p38 and ERK were differentially activated in alveolar macrophages obtained from patients with asbestosis compared with normal subjects. More specifically, p38 was constitutively active and ERK activation was suppressed. Since the upstream pathway leading to ERK was intact, we hypothesized that an ERK-specific phosphatase was, in part, responsible for the decreased ERK activity. We evaluated whether the dual specificity phosphatase MAP kinase phosphatase (MKP)-3, which is highly expressed in the lung and specifically dephosphorylates ERK, was increased after exposure to asbestos. We found that MKP-3 increased after exposure to asbestos, and its expression was regulated by p38. We found that p38 and ERK negatively regulated one another, and MKP-3 had a role in this differential activation. We also found that p38 was a positive regulator and ERK was a negative regulator of TNF-alpha gene expression. Cells overexpressing MKP-3 had a significant increase in TNF-alpha gene expression, suggesting than an environment favoring p38 MAP kinase activation is necessary for TNF-alpha production in monocytes exposed to asbestos. Taken together, these data demonstrate that the p38 MAP kinase down-regulates ERK via activation of MKP-3 in human monocytes exposed to asbestos to enhance TNF-alpha gene expression.