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EDITORIAL FOCUS
Department of Otorhinolaryngology, Laboratory of Clinical Experimental Allergy Research, Malmö University Hospital, Malmö, Sweden
AIRWAY INFECTIONS OF VIRAL or bacterial origin are a common cause of respiratory disease. Infection is also a well-known reason for asthmatic exacerbations (4). Therefore, increased insights in the interaction between pathogens and responsive elements within the respiratory tract may facilitate the development of novel therapeutic approaches. Toll-like receptors (TLRs) comprise an important component of the innate immune system. Ten different TLRs have been characterized in humans. They are all activated by conserved pathogen-associated molecular patterns and believed to induce a proinflammatory response (3). Depending on the pathogen and the site of infection, the interception of infectious agents by the immune system demands separate strategies. Expression of specific TLRs on structural cells of the respiratory system is an essential component in the protection against these pathogens (3). The different cell layers of the airways possess diverse sets of TLRs, each with separate downstream pathways. This architecture of the tissue enables a measured response depending on the nature of pathogen infection. Deeper understanding of the intracellular signal transduction mechanisms downstream of TLRs may be of importance for the treatment of patients with chronic inflammatory conditions of the airways.
Airway smooth muscle cells (ASM) are involved in both hyperreactivity and remodeling in asthmatic patients. ASM cells are highly plastic, and their functional phenotype is altered in response to inflammatory stimuli (5), as reflected in changes in contractility, mass, and ability to release inflammatory mediators (8). In the report from Shan et al., one of the current articles in focus (Ref. 7, see p. L324 in this issue), the authors probe the intracellular mechanisms of TLR stimulation by using an elegant setup that combines dispersed human ASM for analysis of molecular mechanisms and cultured rabbit trachea for obtaining related functional mechanisms. They demonstrate the expression of TLR4 and TLR9 in ASM supporting the previous findings of TLRs in ASM (2, 6) and continue to dissect the role of ERK1/2, p38 MAPK, JNK, and NF-
B following activation of TLRs. Their experiments demonstrate a correlation between the synthetic properties of IL-6 secretion and a shift to a hyperreactive phenotype conveyed by ERK1/2 and opposed by p38 MAPK in a NF-B-dependent manner.
Shan and colleagues (7) used dispersed human ASM to measure secretion of inflammatory mediators such as IL-6 and phosphorylation of different protein kinases in specific cellular compartments. The study of dispersed ASM has the technical disadvantage that the cells lose their contractile phenotype during culture. To overcome this obstacle, culture of airway explants were used. This method offers a possibility for an operator-controlled assay in which defined concentrations and treatment periods of inflammatory agents may interact directly with the airway cells without the influence of circulating leukocytes. The isolation of whole tissue enables individual cells to maintain their original morphological connections, minimizing differentiation and subsequent ablation of contractile capacity (1) obtained in dispersed ASM.
According to Shan and colleagues (7), MAPK ERK1/2 and p38 activation was demonstrated in ASM stimulated with LPS and ISS-ODN, agonists for TLR4 and TLR9, respectively. LPS stimulation induced stronger phosphorylation of ERK1/2 than ISS-ODN, whereas the phosphorylation of p38 was similar for both agonists. This indicates a diverging response to different TLRs, reflecting the activation of separate sets of response elements in ASM. Such dual actions of ERK1/2 and p38 are supported by earlier studies reporting a direct physical interaction between p38
MAPK and ERK1/2 (9) demonstrating that phosphorylation and activation of p38 correlated with inhibition of ERK1/2 phosphotransferase activity. Hence, p38 may sequester ERK1/2 and sterically block their phosphorylation by MEK1.
It is clinically established that different microbes vary in their ability to induce symptomatic airway hyperactivity and asthmatic exacerbations. It is tempting to assume that the authors, by dissecting these intracellular mechanisms, are highlighting an important component in the reaction pattern of ASM. Hence, this may lead to a better understanding and the subsequent development of new pharmacological tools for the benefit of patients with chronic inflammatory airway diseases.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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REFERENCES |
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upregulates 5-HT(2A)-mediated contraction. Br J Pharmacol 137: 971–982, 2002.[CrossRef][ISI][Medline]B signaling pathways. Eur J Immunol 34: 1196–1207, 2004.[CrossRef][ISI][Medline]This article has been cited by other articles:
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  K. Zhang, L. Shan, M. S. Rahman, H. Unruh, A. J. Halayko, and A. S. Gounni Constitutive and inducible thymic stromal lymphopoietin expression in human airway smooth muscle cells: role in chronic obstructive pulmonary disease Am J Physiol Lung Cell Mol Physiol, August 1, 2007; 293(2): L375 - L382. [Abstract] [Full Text] [PDF]
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